endothelin-1 and Pre-Eclampsia

: After examining in Part I the general mechanisms of endothelial cell injury in the kidney, the Working Group on Endothelin and Endothelial Factors of the European Society of Hypertension and the Japanese Society of Hypertension will herein review current knowledge on the role of endothelial dysfunction in multiple disease conditions that affect the kidney, including diabetes mellitus, preeclampsia, solid organ transplantation, hyperhomocysteinemia and antiangiogenic therapy in cancer. The few available randomized controlled clinical trials specifically designed to evaluate strategies for correcting endothelial dysfunction in patients with hypertension and/or chronic kidney disease are also discussed alongside their cardiovascular and renal outcomes.

Topics: Angiogenesis Inhibitors; Animals; Consensus; Diabetic Nephropathies; Endothelin-1; Endothelins; Endothelium, Vascular; Female; Humans; Hyperhomocysteinemia; Hypertension; Kidney; Kidney Transplantation; Pre-Eclampsia; Pregnancy; Renal Insufficiency, Chronic; Vitamin D

Men and women differ in the prevalence, pathophysiology and control rate of hypertension in an age-dependent manner. The renal endothelin system plays a central role in sex differences in blood pressure regulation by control of sodium excretion and vascular function. Improving our understanding of the sex differences in the endothelin system, especially in regard to blood pressure regulation and sodium homeostasis, will fill a significant gap in our knowledge and may identify sex-specific therapeutic targets for management of hypertension.. The current review will highlight evidence for the potential role for endothelin system in the pathophysiology of hypertension within three female populations: (i) postmenopausal women, (ii) women suffering from preeclampsia, or (iii) pulmonary arterial hypertension. Clinical trials that specifically address cardiovascular and renal diseases in females under different hormonal status are limited. Studies of the modulatory role of gonadal hormones and sex-specific mechanisms on critically important systems involved, such as endothelin, are needed to establish new clinical practice guidelines based on systematic evidence.

Topics: Adult; Age Factors; Aged; Blood Pressure; Endothelin-1; Female; Homeostasis; Humans; Hypertension; Kidney; Male; Middle Aged; Postmenopause; Pre-Eclampsia; Pregnancy; Risk Factors; Sex Characteristics; Sodium

Topics: Endothelin-1; Female; Humans; Hypertension; Ischemia; Neovascularization, Pathologic; Oxidative Stress; Placenta; Postpartum Period; Pre-Eclampsia; Pregnancy; Pregnancy Complications, Cardiovascular; Renin-Angiotensin System

Pre-eclampsia (PE) is the most frequently encountered medical complication during pregnancy. It is characterized by a rise in systemic vascular resistance with a relatively low cardiac output and hypovolemia, combined with severe proteinuria. Despite the hypovolemia, renin-angiotensin system (RAS) activity is suppressed and aldosterone levels are decreased to the same degree as renin. This suggests that the RAS is not the cause of the hypertension in PE, but rather that its suppression is the consequence of the rise in blood pressure. Abnormal placentation early in pregnancy is widely assumed to be an important initial event in the onset of PE. Eventually, this results in the release of anti-angiogenic factors [in particular, soluble Fms-like tyrosine kinase-1 (sFlt-1)] and cytokines, leading to generalized vascular dysfunction. Elevated sFlt-1 levels bind and inactivate vascular endothelial growth factor (VEGF). Of interest, VEGF inhibition with drugs like sunitinib, applied in cancer patients, results in a PE-like syndrome, characterized by hypertension, proteinuria and renal toxicity. Both in cancer patients treated with sunitinib and in pregnant women with PE, significant rises in endothelin-1 occur. Multiple regression analysis revealed that endothelin-1 is an independent determinant of the hypertension and proteinuria in PE, and additionally a renin suppressor. Moreover, studies in animal models representative of PE, have shown that endothelin receptor blockers prevent the development of this disease. Similarly, endothelin receptor blockers are protective during sunitinib treatment. Taken together, activation of the endothelin system emerges as an important pathway causing the clinical manifestations of PE. This paper critically addresses this concept, taking into consideration both clinical and preclinical data, and simultaneously discusses the therapeutic consequences of this observation.

Topics: Animals; Endothelin-1; Female; Hemodynamics; Humans; Pre-Eclampsia; Pregnancy; Receptor, Angiotensin, Type 1; Receptors, Endothelin; Renin-Angiotensin System

The morbidity and mortality associated with preeclampsia is staggering. The physiology of the Page kidney, a condition in which increased intrarenal pressure causes hypertension, appears to provide a unifying framework to explain the complex pathophysiology. Page kidney hypertension is renin-mediated acutely and ischemia-mediated chronically. Renal venous outflow obstruction also causes a Page kidney phenomenon, providing a hypothesis for the increased vulnerability of a subset of women who have what we are hypothesizing is a "renal compartment syndrome" due to inadequate ipsilateral collateral renal venous circulation consistent with well-known variation in normal venous anatomy. Dynamic changes in renal venous anatomy and physiology in pregnancy appear to correlate with disease onset, severity, and recurrence. Since maternal recumbent position is well known to affect renal perfusion and since chronic outflow obstruction makes women vulnerable to the ischemic/inflammatory sequelae, heightened awareness of renal compartment syndrome physiology is critical. The anatomic and physiologic insights provide immediate strategies to predict and prevent preeclampsia with straightforward, low-cost interventions that make renewed global advocacy for pregnant women a realistic goal.

Topics: Anatomic Variation; Collateral Circulation; Compartment Syndromes; Endothelin-1; Female; Humans; Ischemia; Kidney; Obesity; Pre-Eclampsia; Pregnancy; Renal Circulation; Renal Veins; Renin; Renin-Angiotensin System; Risk Factors; Sympathetic Nervous System

Preeclampsia (PE) is characterized by hypertension occurring after the twentieth week of pregnancy. It is a significant contributor to maternal and perinatal morbidity and mortality in developing countries and its pervasiveness is increasing within developed countries including the USA. However, the mechanisms mediating the pathogenesis of this maternal disorder and its rising prevalence are far from clear. A major theory with strong experimental evidence is that placental ischemia, resulting from inappropriate remodeling and widening of the maternal spiral arteries, stimulates the release of soluble factors from the ischemic placenta causing maternal endothelial dysfunction and hypertension. Aberrant maternal immune responses and inflammation have been implicated in each of these stages in the cascade leading to PE. Regarding the increased prevalence of this disease, it is becoming increasingly evident from epidemiological data that obesity, which is a state of chronic inflammation in itself, increases the risk for PE. Although the specific mechanisms whereby obesity increases the rate of PE are unclear, there are strong candidates including activated macrophages and natural killer cells within the uterus and placenta and activation in the periphery of T helper cells producing cytokines including TNF-α, IL-6 and IL-17 and the anti-angiogenic factor sFlt-1 and B cells producing the agonistic autoantibodies to the angiotensin type 1 receptor (AT1-aa). This review will focus on the immune mechanisms that have been implicated in the pathogenesis of hypertension in PE with an emphasis on the potential importance of inflammatory factors in the increased risk of developing PE in obese pregnancies.

Topics: Animals; Cytokines; Endothelin-1; Female; Humans; Obesity; Pre-Eclampsia; Pregnancy

Pre-eclampsia is a pregnancy-specific hypertensive disorder that may lead to serious maternal and fetal complications. It is a multisystem disease that is commonly, but not always, accompanied by proteinuria. Its cause(s) remain unknown, and delivery remains the only definitive treatment. It is increasingly recognized that many pathophysiological processes contribute to this syndrome, with different signaling pathways converging at the point of systemic endothelial dysfunction, hypertension, and proteinuria. Different animal models of pre-eclampsia have proven utility for specific aspects of pre-eclampsia research, and offer insights into pathophysiology and treatment possibilities. Therapeutic interventions that specifically target these pathways may optimize pre-eclampsia management and may improve fetal and maternal outcomes. In addition, recent findings regarding placental, endothelial, and podocyte pathophysiology in pre-eclampsia provide unique and exciting possibilities for improved diagnostic accuracy. Emerging evidence suggests that testing for urinary podocytes or their markers may facilitate the prediction and diagnosis of pre-eclampsia. In this review, we explore recent research regarding placental, endothelial, and podocyte pathophysiology. We further discuss new signaling and genetic pathways that may contribute to pre-eclampsia pathophysiology, emerging screening and diagnostic strategies, and potential targeted interventions.

Topics: Adaptive Immunity; Animals; Carbon Monoxide; Carrier Proteins; Endothelin-1; Endothelium, Vascular; Epigenesis, Genetic; Female; Heme Oxygenase (Decyclizing); Humans; Immunity, Innate; Neovascularization, Physiologic; Nitric Oxide; Placenta; Placentation; Podocytes; Pre-Eclampsia; Pregnancy; Receptors, Notch; Renal Insufficiency, Chronic; Signal Transduction

Hypertensive disorders are life-threatening diseases with high morbidity and mortality, affecting billions of individuals worldwide. A multitude of underlying conditions may contribute to hypertension, thus the need for a plethora of treatment options to identify the approach that best meets the needs of individual patients. A growing body of evidence indicates that (1) autoantibodies that bind to and activate the major angiotensin II type I (AT₁) receptor exist in the circulation of patients with hypertensive disorders, (2) these autoantibodies contribute to disease pathophysiology, (3) antibody titers correlate to the severity of the disease, and (4) efforts to block or remove these pathogenic autoantibodies have therapeutic potential. These autoantibodies, termed AT₁ agonistic autoantibodies have been extensively characterized in preeclampsia, a life-threatening hypertensive condition of pregnancy. As reviewed here, these autoantibodies cause symptoms of preeclampsia when injected into pregnant mice. Somewhat surprisingly, these auto antibodies also appear in 3 animal models of preeclampsia. However, the occurrence of AT₁ agonistic autoantibodies is not restricted to pregnancy. These autoantibodies are prevalent among kidney transplant recipients who develop severe transplant rejection and malignant hypertension during the first week after transplantation. AT₁ agonistic autoantibodies are also highly abundant among a group of patients with essential hypertension that are refractory to standard therapy. More recently these autoantibodies have been seen in patients with the autoimmune disease, systemic sclerosis. These 3 examples extend the clinical impact of AT₁ agonistic autoantibodies beyond pregnancy. Research reviewed here raises the intriguing possibility that preeclampsia and other hypertensive conditions are autoimmune diseases characterized by the presence of pathogenic autoantibodies that activate the major angiotensin receptor, AT₁. These pathogenic autoantibodies could serve as presymptomatic biomarkers and therapeutic targets, thereby providing improved medical management for these conditions.

Topics: Animals; Antihypertensive Agents; Autoantibodies; Autoantigens; Biomarkers; Complement Activation; Complement C3a; Cytokines; Dimerization; Disease Models, Animal; Drug Resistance; Endothelin-1; Female; Fetal Growth Retardation; Graft Rejection; Humans; Hypertension; Hypertension, Malignant; Immunization, Passive; Kidney Transplantation; Mice; Placenta; Postoperative Complications; Pre-Eclampsia; Pregnancy; Receptor, Angiotensin, Type 1; Vascular Endothelial Growth Factor Receptor-1

Pulmonary vasoconstriction represents a physiological adaptive mechanism to high altitude. If exaggerated, however, it is associated with important morbidity and mortality. Recent mechanistic studies using short-term acute high altitude exposure have provided insight into the importance of defective vascular endothelial and respiratory epithelial nitric oxide (NO) synthesis, increased endothelin-1 bioavailability, and overactivation of the sympathetic nervous system in causing exaggerated hypoxic pulmonary hypertension in humans. Based on these studies, drugs that increase NO bioavailability, attenuate endothelin-1 induced pulmonary vasoconstriction, or prevent exaggerated sympathetic activation have been shown to be useful for the treatment/prevention of exaggerated pulmonary hypertension during acute short-term high altitude exposure. The mechanisms underpinning chronic pulmonary hypertension in high altitude dwellers are less well understood, but recent evidence suggests that they differ in some aspects from those involved in short-term adaptation to high altitude. These differences have consequences for the choice of the treatment for chronic pulmonary hypertension at high altitude. Finally, recent data indicate that fetal programming of pulmonary vascular dysfunction in offspring of preeclampsia and children generated by assisted reproductive technologies represents a novel and frequent cause of pulmonary hypertension at high altitude. In animal models of fetal programming of hypoxic pulmonary hypertension, epigenetic mechanisms play a role, and targeting of these mechanisms with drugs lowers pulmonary artery pressure. If epigenetic mechanisms also are operational in the fetal programming of pulmonary vascular dysfunction in humans, such drugs may become novel tools for the treatment of hypoxic pulmonary hypertension.

Topics: Acute Disease; Adaptation, Physiological; Altitude Sickness; Anti-Inflammatory Agents; Antihypertensive Agents; Biomarkers; Chronic Disease; Endothelin-1; Female; Fetal Development; Foramen Ovale, Patent; Humans; Hypertension, Pulmonary; Nitric Oxide; Oxidative Stress; Pre-Eclampsia; Pregnancy; Pulmonary Edema; Risk Factors; Sympathetic Nervous System; Vasodilator Agents

Autoantibodies can cause complications in pregnancy. Preeclampsia is the leading cause of maternal and fetal morbidity and mortality during pregnancy. Overall, 5-10% of all pregnancies worldwide develop preeclampsia. Women who developed preeclampsia and their children have an increased risk to suffer from cardiovascular diseases later in life. In preeclampsia, agonistic autoantibodies against the angiotensin II type 1 receptor autoantibodies (AT1-AA) are described. They induce NADPH oxidase and the MAPK/ERK pathway leading to NF-κB and tissue factor activation. AT1-AA are detectable in animal models of preeclampsia and are responsible for elevation of soluble fms-related tyrosine kinase-1 (sFlt1) and soluble endoglin (sEng), oxidative stress, and endothelin-1, all of which are enhanced in preeclamptic women. AT1-AA can be detected in pregnancies with abnormal uterine perfusion and increased resistance index as well as in patients with systemic sclerosis and renal allograft rejection. This review discusses the current knowledge about the AT1-AA, its signaling, and their impact in pregnancy complications and other autoimmune disorders.

Topics: Animals; Antigens, CD; Autoantibodies; Endoglin; Endothelin-1; Enzyme Activation; Female; Humans; MAP Kinase Signaling System; Mice; NADPH Oxidases; NF-kappa B; Oxidative Stress; Pre-Eclampsia; Pregnancy; Pregnancy Complications, Cardiovascular; Rats; Receptor, Angiotensin, Type 1; Receptors, Cell Surface; Thromboplastin; Vascular Endothelial Growth Factor Receptor-1

Preeclampsia is a disorder of hypertension and proteinuria that affects 6 - 8% of normal pregnancies. Recent research has revealed many molecular mechanisms that may contribute to systemic endothelial dysfunction, glomerular capillary endotheliosis, dysregulation of the glomerular filtration apparatus, and podocyte loss. An ischemic placenta elaborates soluble FMS-like tyrosine kinase 1 (sFlt-1), a soluble receptor for vascular endothelial growth factor (VEGF). A variety of mediators, including nitric oxide, Angiotensin II receptor autoantibodies (AT1AA), and endothelin-1 may serve to maintain placental ischemia and systemic endothelial dysfunction. Endothelin-1 and decreased vascular endothelial growth factor may adversely affect overall expression and distribution of podocyte foot process proteins, leading to proteinuria. Podocyte derangements may lead to podocyte apoptosis and loss, as evidenced by the detection of live podocytes and podocyte products in the urine of preeclamptic women. In this review, we explore recent research elucidating the interactions of placenta, endothelium, and podocyte leading to the clinical syndrome of preeclampsia.

Topics: Apoptosis; Autoantibodies; Endothelin-1; Endothelium; Female; Humans; Kidney Glomerulus; Nitric Oxide; Placenta; Podocytes; Pre-Eclampsia; Pregnancy; Receptors, Angiotensin; Signal Transduction; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-1

Endothelin (ET)-1 has been implicated in a diverse range of signalling events in a wide variety of target tissues. Given its potent vasoactive function and the prevalence of hypertension in pre-eclampsia, there has been extensive research on the role of ET-1 in this disorder. Indeed, ET-1 has been suggested to contribute to hypertension in pre-eclampsia. Recently, ET-1 has also been implicated in the induction of both oxidative stress and endoplasmic reticulum stress in pre-eclampsia; each of which has been proposed to contribute to many of the clinical manifestations of this disorder. ET-1 has been shown to activate key signalling molecules that lead to induction of these stress pathways. The use of ET-receptor antagonists could block oxidative and endoplasmic reticulum stress. Hence, further research into the role of ET-1 in pre-eclampsia may lead to the development of possible strategies to circumvent these stress pathways and the associated pathology that occurs in pre-eclampsia. Endothelin (ET)-1 has been implicated in a diverse range of signalling events in a wide variety of target tissues. Given its potent vasoactive function and the prevalence of hypertension in pre-eclampsia, there has been extensive research on the role of ET-1 in this disorder. Indeed, ET-1 has been suggested to contribute to hypertension in pre-eclampsia. Recently, ET-1 has also been implicated in the induction of both oxidative stress and endoplasmic reticulum stress in pre-eclampsia, each of which has been proposed to contribute to many of the clinical manifestations of this disorder. ET-1 has been shown to activate key signalling molecules that lead to induction of these stress pathways. The use of ET-receptor antagonists could block oxidative and endoplasmic reticulum stress. Hence, further research into the role of ET-1 in pre-eclampsia may lead to the development of possible strategies to circumvent these stress pathways and the associated pathology that occurs in pre-eclampsia.

Topics: Adult; Endoplasmic Reticulum; Endothelin Receptor Antagonists; Endothelin-1; Female; Humans; Models, Biological; Oxidative Stress; Pre-Eclampsia; Pregnancy; Signal Transduction; Stress, Physiological

Preeclampsia affects 5%-8% of pregnancies and is the leading worldwide cause of maternal and fetal morbidity and mortality. Preeclampsia is associated with shallow trophoblast invasion and inadequate spiral artery remodeling, which are widely believed to lead to placental hypoxia, the putative culprit initiating the cascade of events that ultimately results in the maternal manifestations of the disease. Despite extensive research, however, the pathophysiology of this disease remains poorly understood, no effective prevention exists, and treatment is limited to symptomatic therapy. Recent research has introduced exciting new theories regarding the pathogenesis of preeclampsia. Clinical and experimental evidence implicating the circulating antiangiogenic molecules soluble Fms-like tyrosine kinase-1 (sFLT-1) and soluble endoglin (sENG), as well as endothelin-1 and the angiotensin II receptor type I autoimmune antibody (AT-1AA), have been especially promising. This review collates evidence for a role of hypoxia and hypoxia-inducible factor-1alpha (HIF1A; referred to as HIF-1α throughout) in the pathogenesis of preeclampsia and discusses possible molecular links between hypoxia and the newly reported potential mediators of the disease's manifestations.

Topics: Animals; Antigens, CD; Autoantibodies; Cell Hypoxia; Endoglin; Endothelin-1; Female; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Placenta; Pre-Eclampsia; Pregnancy; Receptor, Angiotensin, Type 1; Receptors, Cell Surface; Solubility; Vascular Endothelial Growth Factor Receptor-1

Preeclampsia is a pregnancy-induced hypertensive disorder found most commonly in nulliparous women. Recent research performed in animal models of the disease has revealed some of the underlying mechanisms of preeclampsia. Specifically, placental insufficiency and the resulting hypoxia/ischemia have been shown to be crucial to disease progression. In response to placental hypoxia/ischemia, several pathways are activated, which contribute to the clinical manifestations of the disease: increased circulating levels of the anti-angiogenic protein sFlt-1, activation of the maternal inflammatory response, suppressed nitric oxide production, enhanced endothelin-1 production, and induction of reactive oxygen formation. Despite advances in the understanding of the disorder, therapeutic approaches to the treatment of preeclampsia are severely limited. New lines of research, however, indicate some possible new therapeutic approaches for the management of preeclampsia and offer hope for an effective pharmacologic intervention.

Topics: Disease Progression; Endothelin-1; Endothelium, Vascular; Female; Humans; Hypoxia; Inflammation; Phosphodiesterase 5 Inhibitors; Piperazines; Placenta; Pre-Eclampsia; Pregnancy; Purines; Risk Factors; Sildenafil Citrate; Sulfones; Vascular Endothelial Growth Factor A

Preeclampsia is a pregnancy-induced hypertensive disorder characterized by proteinuria and widespread maternal endothelial dysfunction. It remains one of the most common disorders in pregnancy and remains one of the leading causes of maternal and fetal morbidity. Recent research has revealed that placental insufficiency, resulting in hypoxia and ischemia, is a central causative pathway in the development of the disorder. In response, the placenta secretes soluble substances into the maternal circulation which are responsible for the symptomatic phase of the disease. Among the most well characterized factors in the disease pathology are the anti-angiogenic protein soluble fms-like tyrosine kinase-1 (sFlt-1), inflammatory cytokines, and agonistic angiotensin II type-1 receptor autoantibodies. Each of these factors has been shown to induce hypertension experimentally through the production of endothelin-1 (ET-1), a powerful vasoconstrictor. Antagonism of the endothelin-A receptor has proved beneficial in numerous animal models of gestational hypertension, and it remains an intriguing target for pharmacological intervention in preeclampsia.

Topics: Animals; Autoantibodies; Endothelin A Receptor Antagonists; Endothelin-1; Female; Humans; Hypertension, Pregnancy-Induced; Pre-Eclampsia; Pregnancy; Receptor, Angiotensin, Type 1; Vascular Endothelial Growth Factor Receptor-1

Topics: Angiotensin II; Arteriosclerosis; Cardiovascular Diseases; Cell Adhesion Molecules; Coagulants; Diabetes Mellitus; Endothelin-1; Endothelium, Vascular; Female; Humans; Pre-Eclampsia; Pregnancy; Vasoconstrictor Agents; Vasodilator Agents

Low sFlt-1 (soluble Fms-like tyrosine kinase-1) and ET-1 (endothelin-1) levels have been reported in preeclamptic women using proton pump inhibitors.. Here, we examined whether the proton pump inhibitor omeprazole could acutely reduce sFlt-1 and ET-1 (measured as CT-proET-1 [C-terminal pro-endothelin-1]), or increase free PlGF (placental growth factor) in 20 women with confirmed preeclampsia. Primary outcome was specified as the difference in sFlt-1, PlGF, or CT-proET-1 after 4 days of omeprazole versus 20 preeclamptic women not receiving omeprazole.. Administration of omeprazole to women with confirmed preeclampsia does not alter their circulating levels of sFlt-1, PlGF, or ET-1, arguing against a role of this drug as a treatment for this syndrome.

Topics: Adult; Biomarkers; Endothelin-1; Esomeprazole; Female; Humans; Infant; Infant, Newborn; Omeprazole; Placenta; Placenta Growth Factor; Pre-Eclampsia; Pregnancy; Proton Pump Inhibitors; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-1

To investigate the status of lipid peroxidation and serum levels of several vasoactive substances in preeclamptic (PE) pregnant women before and during treatment with magnesium sulfate (MgSO(4)).. The study population included 16 PE women. Circulating levels of malondialdehyde (MDA), endothelin 1 (ET-1), nitric oxide (NO) metabolites, and calcitonin gene-related peptide (CGRP) were measured before (at admission) and during MgSO(4) treatment (at delivery and 24 h postpartum).. At admission systolic and diastolic blood pressures were 157 +/- 3 mm Hg and 106 +/- 2 mm Hg, respectively, and decreased significantly during treatment at delivery and 24 h postpartum (P < 0.0001). Before treatment, serum MDA concentrations were 0.383 +/- 0.037 micromol/L, and decreased significantly during MgSO(4) administration at delivery and 24 h postpartum (P < 0.0001). In contrast, serum ET-1 levels at 24 h postpartum were significantly higher as compared with those observed before treatment (79 +/- 3 versus 65 +/- 2 pg/mL, P = 0.002). Serum NO metabolite concentrations were 26 +/- 3 micromol/L, and no significant changes were observed during treatment. Serum levels of CGRP were 50 +/- 3 pg/mL at admission, and increased significantly at partum (P < 0.001). Serum ET-1 correlated negatively with NO metabolites before treatment (r = -0.69, P = 0.002), but not during treatment. In contrast, ET-1 correlated positively with serum CGRP levels during treatment (r = 0.73, P = 0.002 and r = 0.71, P = 0.002, at delivery and 24 h postpartum, respectively), but not before treatment.. This study demonstrates that MgSO(4) administration to PE pregnant women induced significant changes in lipid peroxidation, production of ET-1 and CGRP.

Topics: Adult; Blood Pressure; Calcitonin Gene-Related Peptide; Endothelin-1; Female; Humans; Lipid Peroxidation; Magnesium Sulfate; Malondialdehyde; Nitric Oxide; Pre-Eclampsia; Pregnancy

The objective of this study was to examine maternal and fetal endothelin-1 (ET-1) in pregnancies complicated with intrauterine growth restriction (IUGR) and to correlate these data with umbilical artery Doppler flow velocity waveforms (FVW). Higher mean maternal (13.8 +/- 6.4 vs 9.2 +/- 3.4 pmol/L, p < 0.05) and fetal (18.5 +/- 9.6 vs 11.7 +/- 6.9 pmol/L, p < 0.05) ET-1 levels were found in pregnancies complicated with IUGR than in controls. Fetal ET-1 level was related to birth weight percentile for gestational week. Maternal and fetal ET-1 concentrations were not related to umbilical artery Doppler flow S/D ratio, PI and RI. Maternal or fetal ET-1 concentrations were also not related to umbilical artery pH, PO2 and PCO2. Pregnancy-induced hypertension was significantly associated with an elevated fetal and maternal ET-1 concentration. In conclusion, increased production and secretion of ET-1 may play a role in the pathophysiology of idiopathic IUGR. Over-production of ET-1 in IUGR is not associated with increased placental resistance as reflected in abnormal umbilical artery Doppler FVW.

Topics: Birth Weight; Endothelin-1; Female; Fetal Growth Retardation; Gestational Age; Humans; Laser-Doppler Flowmetry; Pre-Eclampsia; Pregnancy; Reference Values; Regression Analysis; Ultrasonography; Umbilical Arteries; Vascular Resistance

To evaluate factors contributing to both placental hypoperfusion and maternal vasoconstriction in pre-eclampsia.. Single centre, comparative study of calcium-channel density and affinity in the placental bed of pregnant women with normotension and pre-eclampsia.. Teaching hospital.. Twenty-two primigravidae in the third trimester of pregnancy: 10 with pre-eclampsia and 12 normotensive.. Plasma levels of endothelin-1 (by RIA) and noradrenaline (by HPLC-ED) were measured. Both pharmacological characterisation and anatomical localisation of dihydropyridine-sensitive binding sites (using radioligand-binding studies and autorradiographic techniques) were determined with 3H-isradipine in placental bed tissues to determine both the density (Bmax) and the affinity (Kd) of receptor sites.. Higher plasma levels of endothelin-1 and noradrenalin were found in women with pre-eclampsia compared with normotensive women. Placental bed tissues bound 3H-isradipine in a saturable, reversible time and temperature-dependent manner with very low Kd values. Study of the 3H-isradipine specificity binding included the use of several dihydropyridine displacers. In the group with pre-eclampsia the Scatchard analysis of the results showed a significant increase (P < 0.001) both in the affinity [Kd = 0.23 nmol (0.04) vs 0.45 nmol (0.03), pre-eclampsia vs normotensive] and in the density of calcium-channel binding sites [Bmax = 77.70 fmol/mg (1.30) vs 64.30 fmol/mg (1 80) tissue, pre-eclampsia vs normotensive]. Autoradiography confirmed that in the placental bed tissue of those with pre-eclampsia there was a much higher silver grain density in the arteries walls, compared with normotensive women.. In pre-eclampsia there is an increase in the maternal circulation of two strong vasoconstrictor factors (endothelin-1 and noradrenalin) and a sharp increase both in the density and the affinity of calcium-channel binding sites in placental bed central area. The latter may strongly contribute to the perpetuation of the uteroplacental hypoperfusion either by itself or by amplifying the local actions of circulating factors, such as endothelin-1 and noradrenalin.

Topics: Adult; Autoradiography; Binding Sites; Calcium Channel Blockers; Calcium Channels; Dihydropyridines; Endothelin-1; Female; Humans; Norepinephrine; Placenta; Pre-Eclampsia; Pregnancy; Pregnancy Trimester, Third

The activation of neutrophils was studied in preeclampsia (n = 10) and eclampsia (n = 20) compared to normotensive controls (n = 10) and nonpregnant essential hypertensives (n = 10). Plasma elastase levels were raised in preeclampsia (0.53 +/- 0.32 microgram/mL, P < .002) and eclampsia (1.26 +/- 0.8 microgram/mL, P < .001) respectively compared to normal pregnancies (0.032 +/- 0.009 microgram/mL). The plasma elastases were more elevated in eclamptic cases compared to essential hypertensive (0.53 +/- 0.27 microgram/mL; P = .01) patients. We analyzed the correlation among elastase values, systolic (SBP), mean blood pressures (MBP), endothelin-1 (ET-1) levels and sera cytotoxicity (as measured by fura-2 release from human umbilical venous endothelial cell culture) in eclamptic cases. SBP and MBP were significantly correlated with plasma elastase levels in preeclampsia (r = 0.67, 0.63, respectively; P < .03) and eclampsia (r = 0.49, 0.49, respectively; P < .02). ET-1 levels were correlated with SBP (P = .003) and MBP (P = .001) and corresponding elastase levels (r = 0.606, P < .003) in eclamptic patients. Doses of 10, 25, and 50 pmol/mL of ET-1 increased elastase release in human neutrophil cultures dose and time dependently. Cytotoxicity of eclamptic sera correlated (P < .001) to the corresponding plasma elastase values. Therefore, this study suggests that neutrophil activation and ET-1 induced neutrophil activation occurs in this disease.

Topics: Adult; Blood Pressure; Cell Survival; Cells, Cultured; Eclampsia; Endothelin-1; Endothelium, Vascular; Female; Fluorescent Dyes; Fura-2; Humans; Hypertension; Leukocyte Elastase; Neutrophil Activation; Neutrophils; Pancreatic Elastase; Pre-Eclampsia; Pregnancy

To observe the effects of 3,4-dihydroxyacetophynone (DHAP), one of the constituents of a traditional Chinese herbal medicine, on the activities of endothelial nitric oxide synthetase (NOS) in vascular endothelial cells (VEC) and vascular smooth muscle cells (VSMC) of placenta and the level of endothelin-1 (ET-1) in the plasma from PIH patients.. 22 nulliparous PIH patients were randomly divided into PIH group and DHAP treatment group. Each patients in DHAP group received intravenous administration of DHAP (160-240 mg/d). Blood samples were collected before the administration of DHAP and (or) before cesarean section. The placenta were assayed for nitric oxide synthase activity using histochemical analysis; the concentration of ET in plasma was measured by radioimmunoassays. 10 normal pregnant women or 10 nonpregnant women were served as controls.. In normal pregnant controls, NOS activity was much higher than that in the PIH group; in DHAP group, there was some recovery of NOS activity after DHAP treatment. The concentration of ET was higher in PIH group than that of normal pregnant controls, but it decreased significantly after DHAP therapy (P < 0.05, vs PIH group or before DHAP therapy).. This study indicates that DHAP is effective in the treatment of PIH and its mechanism of action may be due to the adjustment of NO/ET imbalance in PIH patients.

Topics: Acetophenones; Adult; Endothelin-1; Female; Humans; Muscle, Smooth, Vascular; Nitric Oxide Synthase; Placenta; Platelet Aggregation Inhibitors; Pre-Eclampsia; Pregnancy

Preeclampsia (PE) pathogenesis is explained by the two-stage disorder theory. However, mechanisms underlying hypertension and proteinuria in PE remain unclear. The role of (pro)renin receptor (PRR) in PE pathology has received special attention. We examined endothelin-1 (ET-1) production via placental PRR in a PE mouse model.. At 14.5 day-post-coitum (DPC), we performed a reduced uterine perfusion pressure (RUPP) operation, ligating the uterine arteriovenous vessels in female mice. We also infused these mice with a PRR inhibitor, decoy peptide in the handle region of prorenin (HRP) for mice (NH2-RIPLKKMPSV-COOH). At 18.5 DPC, blood, urine, and placenta were collected; fetus and placenta were weighed. We evaluated placental hypoxia using quantitative polymerase chain reaction (PCR), with hypoxia-inducible factor-1α (HIF-1α) as index. We also evaluated PRR, transforming growth factor-β1 (TGF-β1), and ET-1 expression in the placenta using quantitative PCR and western blotting. ET-1 concentration in blood plasma was assessed using enzyme-linked immunosorbent assay.. Blood pressure and proteinuria significantly increased, and fetal and placental weights decreased in RUPP mice. HIF-1α, PRR, TGF-β1, and ET-1 expressions considerably increased in RUPP mice placentas. ET-1 concentration in RUPP mice blood plasma was markedly increased. PRR inhibitor suppressed these changes.. In PE model mice that underwent RUPP treatment, placental hypoxia increased PRR and ET-1 expression suggesting a causative relationship between ET-1 and intracellular PRR signaling. RUPP treatment, when combined with HRP, reversed the effect of elevated ET-1 levels in the model. This study may help to elucidate the pathogenesis of PE considering PRR and ET-1.

Topics: Animals; Disease Models, Animal; Endothelin-1; Female; Mice; Placenta; Pre-Eclampsia; Pregnancy; Prorenin Receptor; Proteinuria; Transforming Growth Factor beta1

Elevated endothelin-1 (ET-1) has been implicated in several diseases including preeclampsia, where it causes the induction of hypertension, oxidative stress, endoplasmic reticulum stress, microvascular dysfunction and tissue damage in different organs. ET-traps are Fc-fusion proteins with a design based on the physiological receptors of ET-1. This paper discusses the potential use of ET-traps as a therapeutic for preeclampsia. ET-traps potently bind and sequester pathologically elevated ET-1 to significantly reduce different markers of pathology to non-disease levels with no toxicity.

Topics: Endothelin-1; Female; Humans; Hypertension; Oxidative Stress; Pre-Eclampsia; Pregnancy

Vascular endothelial growth factor antagonism with angiogenesis inhibitors in cancer patients induces a 'preeclampsia-like' syndrome including hypertension, proteinuria and elevated endothelin (ET)-1. Cyclo-oxygenase (COX) inhibition with aspirin is known to prevent the onset of preeclampsia in high-risk patients. In the present study, we hypothesised that treatment with aspirin would prevent the development of angiogenesis inhibitor-induced hypertension and kidney damage. Our aims were to compare the effects of low-dose (COX-1 inhibition) and high-dose (dual COX-1 and COX-2 inhibition) aspirin on blood pressure, vascular function, oxidative stress, ET-1 and prostanoid levels and kidney damage during angiogenesis-inhibitor therapy in rodents. To this end, Wistar Kyoto rats were treated with vehicle, angiogenesis inhibitor (sunitinib) alone or in combination with low- or high-dose aspirin for 8 days (n=5-7/group). Our results demonstrated that prostacyclin (PGI2) and ET-1 were increased during angiogenesis-inhibitor therapy, while thromboxane (TXA2) was unchanged. Both low- and high-dose aspirin blunted angiogenesis inhibitor-induced hypertension and vascular superoxide production to a similar extent, whereas only high-dose aspirin prevented albuminuria. While circulating TXA2 and prostaglandin F2α levels were reduced by both low- and high-dose aspirin, circulating and urinary levels PGI2 were only reduced by high-dose aspirin. Lastly, treatment with aspirin did not significantly affect ET-1 or vascular function. Collectively our findings suggest that prostanoids contribute to the development of angiogenesis inhibitor-induced hypertension and renal damage and that targeting the prostanoid pathway could be an effective strategy to mitigate the unwanted cardiovascular and renal toxicities associated with angiogenesis inhibitors.

Topics: Angiogenesis Inhibitors; Animals; Aspirin; Cyclooxygenase 1; Cyclooxygenase 2; Endothelin-1; Epoprostenol; Female; Humans; Hypertension; Kidney; Pre-Eclampsia; Pregnancy; Prostaglandin-Endoperoxide Synthases; Rats; Vascular Endothelial Growth Factor A

Patients with preeclampsia demonstrate increases in placental leptin production in midgestation, and an associated increase in late gestation plasma leptin levels. The consequences of mid-late gestation increases in leptin production in pregnancy is unknown. Our previous work indicates that leptin infusion induces endothelial dysfunction in nonpregnant female mice via leptin-mediated aldosterone production and endothelial mineralocorticoid receptor (ECMR) activation, which is ablated by ECMR deletion. Therefore, we hypothesized that leptin infusion in mid-gestation of pregnancy induces endothelial dysfunction and hypertension, hallmarks of clinical preeclampsia, which are prevented by ECMR deletion.. Leptin was infused via miniosmotic pump (0.9 mg/kg per day) into timed-pregnant ECMR-intact (WT) and littermate-mice with ECMR deletion (KO) on gestation day (GD)11-18.. Leptin infusion decreased fetal weight and placental efficiency in WT mice compared with WT+vehicle. Radiotelemetry recording demonstrated that blood pressure increased in leptin-infused WT mice during infusion. Leptin infusion reduced endothelial-dependent relaxation responses to acetylcholine (ACh) in both resistance (second-order mesenteric) and conduit (aorta) vessels in WT pregnant mice. Leptin infusion increased placental ET-1 (endothelin-1) production evidenced by increased PPET-1 (preproendothelin-1) and ECE-1 (endothelin-converting enzyme-1) expressions in WT mice. Adrenal aldosterone synthase (. Collectively, these data indicate that leptin infusion in midgestation induces endothelial dysfunction, hypertension, and fetal growth restriction in pregnant mice, which is ablated by ECMR deletion.

Topics: Animals; Blood Pressure; Endothelin-1; Female; Humans; Hypertension; Leptin; Mice; Mice, Knockout; Placenta; Pre-Eclampsia; Pregnancy; Receptors, Mineralocorticoid

Preeclampsia (PE) is a condition affecting 2-8% of all pregnancies and is a leading cause of perinatal morbidity and mortality. In our study; we aim to investigate the differences in endothelin-1 (ET-1) at both tissue and blood level in the placenta, umbilical cord, and maternal blood obtained from different experimental groups and the changes in the contraction response of umbilical arteries in order to explain how PE affects mother and fetus.. Umbilical cord and placenta samples were obtained from normotensive controls (n = 10) and patients with preeclampsia (n = 10), aged 20-39 years, who delivered by cesarean section at term (between 37 and 39 weeks). All samples were investigated with isolated tissue bath, histopathological, immunohistochemical and real-time PCR methods.. ET-1 messenger RNA expression levels and immunoreactivity were found significantly higher in the PE group while microRNA-1 and microRNA-125b (miR-125b) levels were significantly decreased in placenta compared to control. miR-125b levels were found significantly higher in maternal and umbilical cord blood samples of the PE group. The enlargement in intervillous space, decrease in villous branching, increase in syncytial knots and smaller lumen areas in umblicard cord vessels were also observed. In tissue bath experiments, there were no significant differences in ET-1 responses between groups.. We tried to evaluate molecular mechanisms of PE pathogenesis through expressional regulation and contraction response of ET-1. Although quite abundant work in this field has previously highlighted the importance of ET-1 system, further work is needed to determine the molecular mechanisms underlying expressional regulation of ET-1 in PE.

Topics: Cesarean Section; Endothelin-1; Female; Humans; MicroRNAs; Placenta; Pre-Eclampsia; Pregnancy; RNA, Messenger

Preeclampsia affects ∼2-8% of pregnancies worldwide. It is associated with increased long-term maternal cardiovascular disease risk. This study assesses the effect of the vasoconstrictor N(ω)-nitro-L-arginine methyl ester (L-NAME) in modelling preeclampsia in mice, and its long-term effects on maternal cardiovascular health. In this study, we found that L-NAME administration mimicked key characteristics of preeclampsia, including elevated blood pressure, impaired fetal and placental growth, and increased circulating endothelin-1 (vasoconstrictor), soluble fms-like tyrosine kinase-1 (anti-angiogenic factor), and C-reactive protein (inflammatory marker). Post-delivery, mice that received L-NAME in pregnancy recovered, with no discernible changes in measured cardiovascular indices at 1-, 2-, and 4-wk post-delivery, compared with matched controls. At 10-wk post-delivery, arteries collected from the L-NAME mice constricted significantly more to phenylephrine than controls. In addition, these mice had increased kidney

Topics: Animals; C-Reactive Protein; Cardiovascular Diseases; Disease Models, Animal; Endothelin-1; Female; Matrix Metalloproteinase 9; Mice; NG-Nitroarginine Methyl Ester; Phenylephrine; Placenta; Pre-Eclampsia; Pregnancy; RNA, Messenger; Vascular Endothelial Growth Factor Receptor-1; Vasoconstrictor Agents

Hydroxychloroquine, a drug used for malaria and autoimmune diseases reportedly has beneficial effects against preeclampsia in pregnant women with lupus. However, its mechanism against preeclampsia remains unclear. We investigated the effect of hydroxychloroquine on an Nω-nitro-l-arginine methyl ester-induced preeclampsia rat model.. Pregnant Sprague-Dawley rats were divided into four groups based on treatment (administered on gestational days 7-18): control, Nω-nitro-l-arginine methyl ester, hydroxychloroquine, and Nω-nitro-l-arginine methyl ester plus hydroxychloroquine. All animals were sacrificed on gestational day 19. We assayed tube formation and determined reactive oxygen species levels using human umbilical vein endothelial cells.. Results showed that hydroxychloroquine significantly lowered mean systolic blood pressure (P  < 0.05) in Nω-nitro-l-arginine methyl ester-treated rats. Hydroxychloroquine did not affect their fetal and placental weights. Hydroxychloroquine mitigated Nω-nitro-l-arginine methyl ester-associated changes in proteinuria (P  < 0.05). It normalized plasma soluble fms-like kinase-1 (P  < 0.05) and endothelin-1 (P  < 0.01) levels. In the tube formation assay, hydroxychloroquine increased the total meshes area (P  < 0.05) and mitigated Nω-nitro-l-arginine methyl ester-induced reactive oxygen species formation (P  < 0.05) in human umbilical vein endothelial cells.. We conclude that hydroxychloroquine alleviated hypertension, proteinuria, and normalized soluble fms-like kinase-1 and endothelin-1 levels in our preeclampsia model and that these changes may involve the restoration of endothelial dysfunction; thus, hydroxychloroquine could potentially be used for preventing preeclampsia, even in the absence of lupus.

Topics: Animals; Blood Pressure; Endothelial Cells; Endothelin-1; Female; Hydroxychloroquine; Hypertension; NG-Nitroarginine Methyl Ester; Placenta; Pre-Eclampsia; Pregnancy; Proteinuria; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species

In South Africa, pre-eclampsia (PE) and human immunodeficiency virus (HIV) infection are major causes of pregnancy-related deaths. This study aimed to measure serum levels of endothelin-1 (ET-1), endothelial nitric oxide synthase (eNOS), soluble fms-like tyrosine kinase 1 (sFlt-1), soluble endoglin (sEng) and placental growth factor (PlGF) in HIV-infected highly active antiretroviral therapy (HAART)-treated and HIV-uninfected PE and normotensive women to ascertain if HIV/HAART alters their concentrations. Mean sFlt-1 levels were significantly up-regulated in the PE (HIV-uninfected 4.39 ± 1.29; HIV-infected 5.10 ± 1.10 ng/ml) compared to normotensive women (HIV-uninfected 2.59 ± 0.83; HIV-infected 2.20 ± 0.85 ng/ml). Mean PlGF levels were significantly lower in HIV-uninfected PE vs. HIV-infected normotensive women (29.69 ± 4.47 pg/ml vs. 32.86 ± 6.46 pg/ml;

Topics: Adult; Antiretroviral Therapy, Highly Active; Biomarkers; Case-Control Studies; Endoglin; Endothelin-1; Female; HIV; HIV Infections; Humans; Nitric Oxide Synthase; Placenta Growth Factor; Pre-Eclampsia; Pregnancy; Pregnancy Complications, Infectious; Pregnancy Trimester, Third; South Africa; Vascular Endothelial Growth Factor Receptor-1

Two important clinical features of preeclampsia (PE) are hypertension and fetal growth restriction. The reduced uterine perfusion pressure (RUPP) preclinical rat model of PE exhibits both of these features. Moreover, RUPP and PE women have elevated vasoconstrictor peptide endothelin-1 (ET-1) and inflammation. Interleukin-2 (IL-2) is a cytokine that regulates NK cell activity and is elevated in miscarriage, PE, and RUPP rats. The objective of this study was to examine a role for IL-2 in NK cell activation, fetal growth restriction, and hypertension during pregnancy by either infusion of IL-2 or blockade of IL-2 (basiliximab) in normal pregnant (NP) and RUPP rats. On gestational day 14, NP and RUPP rats received low (LD), middle (MD), or high dose (HD) IL-2 (0.05, 0.10, or 0.20 ng/ml) IP or basiliximab (0.07 mg per rat) by IV infusion. On day 19, blood pressure (MAP), pup weights, and blood were collected. Basiliximab had no effect on blood pressure, however, significantly lowered NK cells and may have worsened overall fetal survival in RUPP rats. However, IL-2 LD (102 ± 4 mmHg) and IL-2 HD (105 ± 6 mmHg) significantly lowered blood pressure, ET-1, and activated NK cells compared to control RUPPs (124 ± 3 mmHg, p < 0.05). Importantly, IL-2 in RUPP rats significantly reduced fetal weight and survival. These data indicate that although maternal benefits may have occurred with low dose IL-2 infusion, negative effects were seen in the fetus. Moreover, inhibition of IL-2 signaling did not have favorable outcome for the mother or fetus.

Topics: Animals; Basiliximab; Blood Pressure; Endothelin-1; Female; Fetal Growth Retardation; Immunity, Innate; Interleukin-2; Ischemia; Placenta; Pre-Eclampsia; Pregnancy; Rats; Rats, Sprague-Dawley; Sex Characteristics

Pre-eclampsia, one of the major disorders of pregnancy, is characterized by inadequate trophoblast invasion and defective trophoblast-mediated remodeling of placental vasculature. Hypoxia-inducible transcription factor (HIF)-2α plays a critical role in regulating cellular function of trophoblasts; however, its role in placental development and in the pathogenesis of pre-eclampsia remains elusive. CCK-8 assay was used to detect cell viability. Invasion assay was performed to determine the effect of HIF-2α on trophoblast function. Flow cytometry was used for detecting apoptosis and cell cycle. The mRNA and protein expressions of HIF-2α, VEGF, iNOS, and ET-1 were determined by quantitative real-time PCR and western blot techniques. The roles of HIF-2α in JEG-3 trophoblast cells were examined using siRNA technology. The presence of HIF-2α siRNA reduced the levels of cell viability after 48 h incubation, and the cell viability further reduced at 72 h. Besides, HIF-2α siRNA enhanced trophoblast apoptosis, as determined by flow cytometric measurement. Increased G1-phase and decreased S-phase cell population were induced by HIF-2α siRNA based on the determination of cell cycle distribution using propidium iodide staining. Furthermore, the invasive ability of JEG-3 trophoblasts was significantly reduced by HIF-2α siRNA. In addition, knockdown of the HIF-2α gene significantly decreased VEGF, iNOS, and ET-1 levels in JEG-3 human trophoblasts. Our findings provide preliminary evidence of the functions of HIF-2α in trophoblast biology and suggest that the downregulation of HIF-2α enhances cell apoptosis and limits trophoblast invasion.

Topics: Apoptosis; Basic Helix-Loop-Helix Transcription Factors; Cell Line; Cell Movement; Down-Regulation; Endothelin-1; Female; Humans; Nitric Oxide Synthase Type II; Pre-Eclampsia; Pregnancy; Signal Transduction; Trophoblasts; Vascular Endothelial Growth Factor A

Placental blood vessels play important roles in maternal-fetal circulation. Although pathologic mechanisms of preeclampsia are unclear, it is known that placental vascular dysfunction could contribute to pregnant hypertension. However, placental micro-vessel function or dysfunction at preterm has not been investigated.. Human placentas from normal and preeclamptic pregnancies at preterm and term were obtained. Placental micro-vessels were used for determining vascular tension and responses to various vasoconstrictors as well as intracellular calcium store capability. It was the first time to show vascular responses in placental arteries to angiotensin II, endothelin-1, and other vascular drugs at preterm.. Compared to the control, placental vascular contractile responses to angiotensin II and caffeine were significantly decreased, while placental vascular responses to KCl, endothelin-1, and bradykinin were not significantly altered in the later term group in preeclampsia. In comparison of placental micro-vessel tension between the preterm and later term, caffeine- and serotonin-induced vascular contractions were significantly weaker in the preterm than that in the later term. On the contrary, vascular response to angiotensin II was increased in the preterm preeclampsia, while KCl-, endothelin-1, and bradykinin-mediated placental vessel responses in the preterm preeclampsia were similar to that in later term preeclampsia.. New data showed that micro-vessel responses to angiotensin II and serotonin, not endothelin- 1 or bradykinin, were significantly reduced in the human placentas at preterm, and intracellular Ca2+ store capacity was damaged too, providing important information on possible contributions of placental vascular dysfunction to pregnant hypertension.

Topics: Angiotensin II; Arteries; Endothelin-1; Female; Humans; In Vitro Techniques; Infant, Newborn; Microvessels; Placenta; Pre-Eclampsia; Pregnancy; Premature Birth; Serotonin; Term Birth; Vasoconstriction; Vasoconstrictor Agents

To explore the potential correlation between endothelin 1 (EDN1) gene polymorphisms with preeclampsia (PE).. The single nucleotide polymorphisms (SNPs) of 248 PE patients and 232 healthy controls were genotyped by Polymerase Chain Reaction (PCR). The possible association between EDN1 polymorphisms and PE was revealed through the t-test and the Chi-square test.. PE risk was significantly correlated with the C allele of polymorphism rs5370 in EDN1. The polymorphism rs5370 in EDN1 was remarkably associated with the onset of severe PE, rather than mild PE. The markedly increased risk of early-onset PE was related to the C allele of polymorphism rs5370 in EDN1, while no significant difference in the allele frequency of polymorphism rs1800541 was detected between the PE group and the control group. In the co-dominant model, the CC genotype of polymorphism rs5370 in EDN1 was associated with the increased PE risk. PE risk in the population carrying TC genotype was 1.59 times higher than those with TT/CC genotype, while polymorphism rs1800541 had no apparent association with PE risk. In the severe PE group, there was an evident difference in the genotype frequency between the dominant and over-dominant models of polymorphism rs5370. In the recessive model, the raised risk of early-onset PE was notably correlated with the TT/CC genotype compared with that of TT genotype. However, no evident association with the genotype frequency of polymorphism rs1800541 was observed between PE patients and controls.. EDN1 gene polymorphism rs5370 is correlated with the increased risk of PE.

Topics: Adolescent; Adult; Case-Control Studies; Endothelin-1; Female; Genetic Predisposition to Disease; Genotype; Humans; Middle Aged; Polymorphism, Single Nucleotide; Pre-Eclampsia; Pregnancy; Young Adult

There is avid interest in pravastatin as a therapeutic intervention for pre-eclampsia, however little is known on statin action on endothelial dysfunction. This study aimed to evaluate the ability of pravastatin, simvastatin and rosuvastatin to reduce pre-eclampsia-associated markers of endothelial dysfunction in human endothelial cells.. Primary human umbilical vein endothelial cells (HUVECs) and uterine microvascular cells (UtMVs) were isolated and treated with 0.2, 2, 20 and 200 µM pravastatin, simvastatin and rosuvastatin for 24 h, either with or without pre-treatment with TNF-α to induce endothelial dysfunction.. Cell viability (MTS) assays were performed and cells were visually inspected. Expression of endothelial dysfunction markers, endothelin-1 (ET-1) and vascular cell adhesion molecule-1 (VCAM-1) were assessed by qPCR (n=3). Intracellular VCAM-1 protein was examined by Western Blotting (n=5). ET-1 and soluble fms-like tyrosine kinase-1 (sFLT-1) protein secretion was assessed by ELISA in HUVEC conditioned media (n=3).. High doses of simvastatin and rosuvastatin significantly compromised HUVEC survival. 200 µM simvastatin significantly reduced UtMV survival. Abnormal cell structure was observed with these doses and thus were excluded from further analysis. The statins did not mitigate TNF-α induced ET-1 or VCAM-1 expression in either HUVECs or UtMVs, nor VCAM-1 protein expression in HUVECs. 0.2 µM pravastatin and simvastatin significantly reduced ET-1 and sFLT-1 protein secretion.. Pravastatin significantly reduced secretion of both ET-1 and sFLT-1, key mediators of endothelial dysfunction. Importantly, pravastatin had no toxic effects, in contrast to rosuvastatin and simvastatin. This further supports selection of pravastatin for clinical applications to combat pre-eclampsia.

Topics: Cell Survival; Cells, Cultured; Endothelin-1; Endothelium, Vascular; Female; Human Umbilical Vein Endothelial Cells; Humans; Pravastatin; Pre-Eclampsia; Pregnancy; Rosuvastatin Calcium; Simvastatin; Vascular Cell Adhesion Molecule-1; Vascular Endothelial Growth Factor Receptor-1

Levels of leptin and marinobufagenin (MBG), a cardiotonic steroid, are elevated in the serum of women with pre-eclampsia. Besides this, leptin administration to pregnant rats increases systolic blood pressure (SBP), urinary protein excretion and serum markers of endothelial activation. The link between leptin and MBG is unknown and it is also unclear if leptin-induced increases in blood pressure and proteinuria in the pregnant rat could be prevented by an MBG antagonist. To ascertain this link, this study investigated the effect of resibufogenin (RBG), a marinobufagenin antagonist, on leptin-induced increases in blood pressure and proteinuria during pregnancy in rats. Four groups of Sprague-Dawley rats, aged 12 weeks, were given either normal saline (CONTROL) or 120 μg/kg/day of leptin (LEP), or 120 μg/kg/day of leptin+30 μg/kg/day of resibufogenin (L + RBG) or 30 μg/kg/day of resibufogenin (RBG) from Day 1-20 of pregnancy. Systolic blood pressure and urinary protein excretion (UPE) were measured during the study period. Animals were euthanized on day 21 of pregnancy and vascular cell adhesion molecule 1, (VCAM-1), soluble intracellular cell adhesion molecule 1 (sICAM-1), E-selectin and endothelin-1 (ET-1) were estimated in the serum. SBP, UPE, VCAM-1, sICAM-1 and ET-1 were significantly higher only in the LEP group when compared with those in CONT and in L + RBG and RBG groups. The prevention by RBG of leptin-induced increases in SBP, proteinuria, and endothelial activation during pregnancy seem to suggest a potential role for MBG in leptin-induced adverse effects on blood pressure, urinary protein excretion and endothelial activity during pregnancy in the rat.

Topics: Animals; Blood Pressure; Bufanolides; Endothelin-1; Endothelium, Vascular; Female; Intercellular Adhesion Molecule-1; Leptin; Pre-Eclampsia; Pregnancy; Proteinuria; Rats; Rats, Sprague-Dawley; Vascular Cell Adhesion Molecule-1

The antiangiogenic factors soluble fms-like tyrosine kinase-1 (sFlt-1) and soluble endoglin (sENG) are elevated in preeclampsia and have been implicated in its pathogenesis. We have previously demonstrated metformin and sulfasalazine independently reduce antiangiogenic factor secretion. Here we examined whether combining metformin and sulfasalazine may be more effective than either alone in reducing placental expression and secretion of antiangiogenic and angiogenic factors and the expression of markers of endothelial dysfunction.. We performed functional experiments using primary human placenta to explore the effect of metformin and sulfasalazine, at lower doses than previously explored, individually and in combination, on sFlt-1 and sENG secretion and placental growth factor (PlGF) and vascular endothelial growth factor (VEGFα) expression. Using primary endothelial cells we induced dysfunction using cytokine tumor necrosis factor-α (TNF-α) and assessed the effect of low dose combination treatment on the expression of vascular cell adhesion molecule-1 (VCAM-1) and Endothelin-1 (a potent vasoconstrictor).. We demonstrated combination metformin and sulfasalazine was additive in reducing sFlt-1 secretion from cytotrophoblasts and placental explants. Combination treatment was also additive in reducing sENG secretion from placental explants. Furthermore, combination treatment increased cytotrophoblast VEGFα mRNA expression. Whilst combination treatment increased PlGF mRNA expression this was similar to treatment with sulfasalazine alone. Combination therapy reduced TNFα induced endothelin-1 mRNA expression however did not change VCAM expression.. Low dose combination metformin and sulfasalazine reduced cytotrophoblast sFlt-1 and sENG secretion, increased VEGFα expression and reduced TNFα induced endothelin-1 expression in primary endothelial cells. Combination therapy has potential to treat preeclampsia.

Topics: Drug Therapy, Combination; Endoglin; Endothelin-1; Female; Humans; Metformin; Placenta; Placenta Growth Factor; Pre-Eclampsia; Pregnancy; Sulfasalazine; Vascular Cell Adhesion Molecule-1; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-1

To study the correlation between circulating microRNA-206 (miR-206) levels and endothelin-1 (ET-1) levels, and to explore its association with preeclampsia (PE) risk.Reverse transcription-PCR (RT-PCT) was used to compare the plasma miR-206 levels in 200 PE patients and 200 healthy controls. The correlation between miR-206 and ET-1 levels in plasma of PE patients was analyzed by Pearson analysis. MiR-206 was transfected into human umbilical vein endothelial cells cells and ET-1 expression was analyzed by enzyme-linked immunosorbent assay.RT-PCR results showed that plasma miR-206 levels in PE patients were significantly higher than those in the control group (P < .01). The results of receiver operating characteristic curve analysis showed that the area under the curve of plasma miR-206 level in the diagnosis of PE was 0.94 (95% confidence interval: 0.92-0.96). Plasma ET-1 levels in PE patients were significantly lower than those in the control group by enzyme-linked immunosorbent assay (P < .01). The area under the curve of plasma ET-1 level in the diagnosis of PE was 0.92 (95% confidence interval: 0.90-0.95). The level of miR-206 in plasma was negative correlated with ET-1 level (r = -0.37, P < .01). The expression level of ET-1 was significantly decreased in human umbilical vein endothelial cells cells transfected with miR-206.miR-206 can down-regulate the expression of EDN1 gene, which may be related to the increased risk of preeclampsia.

Topics: Adult; Down-Regulation; Endothelin-1; Enzyme-Linked Immunosorbent Assay; Female; Gene Expression; Humans; MicroRNAs; Pre-Eclampsia; Pregnancy; Real-Time Polymerase Chain Reaction; ROC Curve

The aim is to analyze the value of endothelial dysfunction markers during pregnancy.. Materials and methods: We have examined 153 pregnant women to identify endothelial dysfunction markers of endothelin-1, nitrogen oxide (NO) that have been studiedusing immunoenzymometric sets for an uncomplicated and complicated pregnancy.. Results: We found that the concentration of endothelin-1 repeatedly exceeded the rates in pregnant women with miscarriages than during physiological pregnancy. The diametrically opposite pattern concerns the level of nitrogen oxide. These changes in the markers of the functional state of the endothelin indicate the development of the dysfunction of this system in women with the pathology of pregnancy.. Conclusions: Consequently, endothelial dysfunction can be considered to be one of the reasons for miscarriage in the examined women. Therefore, the definition of markersof endothelial dysfunction has prognostic value.

Topics: Abortion, Spontaneous; Biomarkers; Endothelin-1; Female; Humans; Pre-Eclampsia; Pregnancy; Vascular Diseases

Preeclampsia is a prevalent pregnancy complication characterized by new-onset maternal hypertension and inflammation, with placental ischemia as the initiating event. Studies of others have provided evidence for the importance of lymphocytes in placental ischemia-induced hypertension; however, the contributions of B1 versus B2 lymphocytes are unknown. We hypothesized that peritoneal B1 lymphocytes are important for placental ischemia-induced hypertension. As an initial test of this hypothesis, the effect of anti-CD20 depletion on both B-cell populations was determined in a reduced utero-placental perfusion pressure (RUPP) model of preeclampsia. Anti-murine CD20 monoclonal antibody (5 mg/kg, Clone 5D2) or corresponding mu IgG2a isotype control was administered intraperitoneally to timed pregnant Sprague-Dawley rats on gestation day (GD)10 and 13. RUPP or sham control surgeries were performed on GD14, and mean arterial pressure (MAP) was measured on GD19 from a carotid catheter. As anticipated, RUPP surgery increased MAP and heart rate and decreased mean fetal and placental weight. However, anti-CD20 treatment did not affect these responses. On GD19, B-cell populations were enumerated in the blood, peritoneal cavity, spleen, and placenta with flow cytometry. B1 and B2 cells were not significantly increased following RUPP. Anti-CD20 depleted B1 and B2 cells in peritoneum and circulation but depleted only B2 lymphocytes in spleen and placenta, with no effect on circulating or peritoneal IgM. Overall, these data do not exclude a role for antibodies produced by B cells before depletion but indicate the presence of B lymphocytes in the last trimester of pregnancy is not critical for placental ischemia-induced hypertension.

Topics: Animals; Antibodies, Monoclonal; Antigens, CD20; Arterial Pressure; B-Lymphocyte Subsets; Disease Models, Animal; Endothelin-1; Female; Fetal Growth Retardation; Gestational Age; Immunoglobulin M; Lymphocyte Depletion; Placental Circulation; Pre-Eclampsia; Pregnancy; Rats, Sprague-Dawley

An association between preeclampsia and (pro)renin was recently reported. Intracellular signaling of the (pro) renin receptor [(P)RR] increases the expressions of TGF-β and PAI-1. In this study we sought to clarify the involvement of (pro)renin in the pathogenesis of preeclampsia via the intracellular signaling of (P)RR on preeclampsia placentas. Activated (pro)renin plasma concentrations were compared between pregnant women with (n=15) and without (n=28) preeclampsia. The placentas were immunohistochemically evaluated with anti-HIF-1α and anti-(P)RR antibodies. HTR-8/SVneo cells were cultured under hypoxic conditions and treated with human recombinant (pro)renin. The mRNA expressions of HIF-1α, (P)RR, PAI-1, TGF-β, and ET-1 were also examined by real-time RCR. The activated (pro)renin plasma concentration was significantly higher in the third vs. the second trimester in the preeclampsia patients. HIF-1α and (P)RR expressions were significantly increased in the preeclampsia placentas. The mRNA expressions of PAI-1, TGF-β, and ET-1 were significantly increased in the experiments using recombinant (pro)renin vs. hypoxic conditions. (P)RR expression in preeclampsia placentas is increased by persistent hypoxia through the second and third trimesters, and PAI-1, TGF-β, and ET-1 production is increased via (P)RR. Our results suggest that ET-1 production via the intracellular signaling of (P)RR is important in the pathogenesis of preeclampsia.

Topics: Adult; Cells, Cultured; Endothelin-1; Female; Humans; Plasminogen Activator Inhibitor 1; Pre-Eclampsia; Pregnancy; Prorenin Receptor; Receptors, Cell Surface; Signal Transduction; Transforming Growth Factor beta

The content of vasoactive compounds and arachidonic acid in the placenta and amniotic fluid was studied in full-term (39-40 weeks) physiological pregnancy and preeclampsia (PE). The content of metabolites of nitric oxide (NOx), endothelin-1, thromboxane B2 (TxB2), prostacycline (PGI2) and arachidonic acid was estimated using spectrophotometric, immunoenzyme methods and gas-liquid chromatography. It was found that in PE the content of vasoconstrictors, of endothelin and TxB2, increased in the placenta and amniotic fluid, while the content of vasodilators, PGI2 and NOx decreased. Despite the same directionality of changes in both studied objects, the degree of changes differed and was more pronounced in the placenta. A direct or inverse correlative relationship was found between various vasoactive components (depending on their effect on vascular tone). In the case of arachidonic acid changes in its content in PE correlated with the level of vasoactive compounds, the source of which it is. The revealed differences in the ratio of vasoactive components obviously play a pathogenetic role in the development of PE and its subsequent complications.. Izucheno soderzhanie vazoaktivnykh soedineniĭ i arakhidonovoĭ kisloty v platsente i okoloplodnykh vodakh pri donoshennoĭ (39-40 nedel') fiziologicheskoĭ beremennosti i preéklampsii (PÉ). S pomoshch'iu spektrofotometricheskikh, immunofermentnykh metodov i gazozhidkostnoĭ khromatografii otsenivali soderzhanie metabolitov oksida azota (NOx), éndotelina-1 (ÉT-1), tromboksana B2 (TxB2), prostatsiklina (PGI2) i arakhidonovoĭ kisloty. Ustanovleno, chto pri PÉ kolichestvo vazokonstriktorov ÉT-1 i TxB2 vozrastaet v platsente i okoloplodnykh vodakh, a vazodilatatorov – NOx i PGI2 snizhaetsia. Na fone odinakovoĭ napravlennosti izmeneniĭ v oboikh issledovannykh ob"ektakh stepen' izmeneniia razlichna i bolee vyrazhena v platsente. Mezhdu razlichnymi vazoaktivnymi komponentami obnaruzhena priamaia ili obratnaia korreliatsionnaia vzaimosviaz' (v zavisimosti ot ikh vliianiia na sosudistyĭ tonus). Izmenenie soderzhaniia arakhidonovoĭ kisloty pri PÉ korrelirovalo s urovnem vazoaktivnykh soedineniĭ, istochnikom kotorykh ona iavliaetsia. Vyiavlennye otlichiia v sootnoshenii vazoaktivnykh komponentov, ochevidno, igraiut patogeneticheskuiu rol' v razvitii PÉ i ee posleduiushchikh oslozhneniĭ.

Topics: Amniotic Fluid; Arachidonic Acid; Endothelin-1; Female; Humans; Nitric Oxide; Placenta; Pre-Eclampsia; Pregnancy; Prostaglandins I; Thromboxane B2

This chapter describes the methodologies which may be used in evaluating in vitro endothelial cell dysfunction in preeclampsia.

Topics: Activins; Cells, Cultured; Endothelial Cells; Endothelin-1; Enzyme-Linked Immunosorbent Assay; Female; Follistatin; Human Umbilical Vein Endothelial Cells; Humans; Intercellular Adhesion Molecule-1; Pre-Eclampsia; Pregnancy; Radioimmunoassay; Vascular Cell Adhesion Molecule-1

Topics: Animals; Arterial Pressure; Bilirubin; Biliverdine; Boranes; Carbonates; Cells, Cultured; Disease Models, Animal; Endothelial Cells; Endothelin-1; Enzyme Induction; Female; Heme Oxygenase-1; Ischemia; Kidney Glomerulus; Placenta; Placental Circulation; Pre-Eclampsia; Pregnancy; Protoporphyrins; Rats, Sprague-Dawley; Tumor Necrosis Factor-alpha

In a recent issue of Clinical Science, Stanhewicz et al. investigated persistent microvascular dysfunction in women up to 16 months postpartum. The authors found sensitivity to the pressor effects of endothelin-1 (ET-1) was enhanced when compared with women who had a normotensive pregnancy. Importantly, the authors demonstrated that this effect was mediated via the endothelin type B (ET

Topics: Cardiovascular Diseases; Endothelin-1; Endothelins; Female; Humans; Pre-Eclampsia; Pregnancy; Receptor, Endothelin B

Topics: Albuminuria; Analysis of Variance; Animals; Blood Pressure Determination; Endothelin-1; Female; Gene Expression Regulation, Developmental; Immunohistochemistry; Mice; Mice, Inbred C57BL; Pre-Eclampsia; Pregnancy; Pregnancy, Animal; Real-Time Polymerase Chain Reaction; Reference Values; Risk Assessment; Vascular Endothelial Growth Factor Receptor-1

Preeclampsia (PE), associates with long-term increased risk for cardiovascular disease in women, suggesting that PE is not an isolated disease of pregnancy. It is not known if increased risk for long-term diseases is due to PE-specific factors or to prepregnancy renal and cardiovascular risk factors. We used a mouse model in which a WT female with normal prepregnancy health develops PE to investigate if preeclampsia causes long-term cardiovascular consequences after pregnancy for mothers and offspring. Mothers exhibited endothelial dysfunction and hypertension after PE and had glomerular injury that not only persisted but deteriorated, leading to fibrosis. Left ventricular (LV) remodeling characterized by increased collagen deposition and MMP-9 expression and enlarged cardiomyocytes were also detected after PE. Increased LV internal wall thickness and mass, increased end diastolic and end systolic volumes, and increased stroke volume were observed after PE in the mothers. Placenta-derived bioactive factors that modulate vascular function, markers of metabolic disease, vasoconstrictor isoprostane-8, and proinflammatory mediators were increased in sera during and after a preeclamptic pregnancy in the mother. Offspring of PE mice developed endothelial dysfunction, hypertension, and signs of metabolic disease. Microglia activation was increased in the neonatal brains after PE, suggesting neurogenic hypertension in offspring. Prevention of placental insufficiency with pravastatin prevented PE-associated cardiovascular complications in both mothers and offspring. In conclusion, factors that develop during PE have long-term, cardiovascular effects in the mother and offspring independent of prepregnancy risk factors.

Topics: Animals; Cardiovascular Diseases; Disease Models, Animal; Endothelin-1; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypertension; Male; Mice; Mice, Inbred C57BL; Placenta; Pravastatin; Pre-Eclampsia; Pregnancy; Risk Factors; Vascular Remodeling

Preeclampsia is a major cause of maternal and fetal morbidity and mortality worldwide. It is a multisystem pregnancy syndrome characterized by general endothelial dysfunction caused mainly by plasma factors and debris in endothelial cells. It is widely accepted that endothelin-1 (ET-1) is involved in the pathophysiology of preeclampsia, and so it is of interest to ascertain whether the ET-1 gene (EDN1) can be targeted with tools such as miRNAs. Therefore, we investigated the relationship between the expression of miRNAs that putatively target EDN1 (and so affect ET-1 levels) in HUVECs incubated with plasma from preeclamptic women. EDN1 expression and ET-1 levels in HUVECs incubated with plasma from women with preeclampsia were similar to those in plasma from healthy pregnant women. Expression of miRNAs let-7a, -7b, and -7c, and to a lesser degree 125a and 125b, was increased in preeclampsia. Expression of miRNAs of the let-7 family was significantly negatively correlated with ET-1 levels in preeclampsia. Transfection of the preeclampsia cultures with mimic miRNA let-7 decreased ET-1 levels. Our findings show that preeclamptic plasma stimulates the expression of miRNAs in HUVECs, leading to a decrease in ET-1levels, which suggests that therapeutic miRNAs may aid in the management of preeclampsia.

Topics: Adult; Case-Control Studies; Cells, Cultured; Down-Regulation; Endothelin-1; Female; Human Umbilical Vein Endothelial Cells; Humans; MicroRNAs; Pre-Eclampsia; Pregnancy; Young Adult

Patients with preeclampsia display elevated placenta-derived sFlt-1 (soluble Fms-like tyrosine kinase-1) and endoglin levels and decreased placental growth factor levels. Proton pump inhibitors (PPIs) decrease trophoblast sFlt-1 and endoglin secretion in vitro. PPIs are used during pregnancy to combat reflux disease. Here, we investigated whether PPIs affect sFlt-1 in women with confirmed/suspected preeclampsia, making use of a prospective cohort study involving 430 women. Of these women, 40 took PPIs (6 esomeprazole, 32 omeprazole, and 2 pantoprazole) for 8 to 45 (median 29) days before sFlt-1 measurement. Measurements were only made once, at study entry between weeks 20 and 41 (median 33 weeks). PPI use was associated with lower sFlt-1 levels, with no change in placental growth factor levels, both when compared with all non-PPI users and with 80 gestational age-matched controls selected from the non-PPI users. No sFlt-1/placental growth factor alterations were observed in women using ferrous fumarate or macrogol while, as expected, women using antihypertensive medication displayed higher sFlt-1 levels and lower placental growth factor levels. The PPI use-associated decrease in sFlt-1 was independent of the application of antihypertensive drugs and also occurred when restricting our analysis to patients with hypertensive disease of pregnancy at study entry. PPI users displayed more cases with preexisting proteinuria, less gestational hypertension, and a lower number of neonatal sepsis cases. Finally, their plasma endoglin and endothelin-1 levels were lower while sFlt-1 levels correlated positively with both. In conclusion, PPI use associates with low sFlt-1, endoglin, and endothelin-1 levels, warranting prospective trials to investigate the therapeutic potential of PPIs in preeclampsia.

Topics: Adult; Blood Pressure Determination; Cohort Studies; Endoglin; Endothelin-1; Female; Gastroesophageal Reflux; Gestational Age; Humans; Netherlands; Placental Function Tests; Pre-Eclampsia; Pregnancy; Prospective Studies; Proton Pump Inhibitors; Vascular Endothelial Growth Factor Receptor-1

The ET system might be involved in the pathogenesis of hypertensive disorders during pregnancy. The objective is to analyse the impact of ET-1 in hypertensive pregnant women by a strict meta-analysis of published human clinical studies.. Based on the principle of Cochrane systematic reviews, Cohort studies in PubMed (Medline), Google Scholar and China Biological Medicine Database (CBM-disc) designed to identify the role of endothelin-1 (ET-1) in the pathophysiology of gestational hypertension and preeclampsia were screened. Review Manager Version 5.0 (Rev-Man 5.0) was applied for statistical analysis. Mean difference and 95% confidence interval (CI) were shown in inverse variance (IV) fixed-effects model or IV random-effects model.. Sixteen published cohort studies including 1739 hypertensive cases and 409 controls were used in the meta-analysis. ET-1 plasma concentrations were higher in hypertensive pregnant women as compared to the controls (mean difference between groups: 19.02 [15.60～22.44], P < 0.00001,). These finding were driven by severity of hypertension and/or degree of proteinuria.. Plasma ET-1 concentrations are elevated in hypertensive disorders during human pregnancy. In particular women with preeclampsia (hypertensive pregnant women with proteinuria) have substantially elevated plasma ET-1 concentration as compared to pregnant women with normal blood pressure.

Topics: Endothelin-1; Female; Humans; Hypertension; Hypertension, Pregnancy-Induced; Pre-Eclampsia; Pregnancy; Pregnancy Complications; Proteinuria

The markers of endothelium dysfunction and factors of inflammation in pregnant women with hypertension with hypertension disorders of various genesis were analyzed. The clinical laboratory study was carried out on the basis of sampling of 158 women at pregnancy period of22-3 7 weeks. Out of this sampling 30 women had previously present chronic arterial hypertension, 3 0 women had chronic arterial hypertension and consecutive preeclampsia, 43 women had preeclampsia and 55 women had uncomplicated course of pregnancy without hypertension disorders (control group). It is established that in pregnant women with hypertension disorders of various genesis endothelial dysfunction and inflammation are developed/ This occurrence is confirmed by increasing of in blood of number of circulating desquamated endotheliocytes, C-reactive protein and homocystein in all groups; by increasing of serum level of t-PA, endothelin (1-21), MMP-2, sVCAM-1 and IL-6 under preeclampsia, including one consecutive to chronic arterial hypertension; by increasing of content of IL-6 in blood serum under chronic arterial hypertension with consecutive preeclampsia. The criteria are developed concerning serum content of t-PA, sVCAM-1, endothelin (1-21) and MMP-2 permitting to diagnose differentially previously present hypertension and preeclampsia, including consecutive one to chronic arterial hypertension.

Topics: Adult; Biomarkers; Endothelin-1; Endothelium; Female; Humans; Hypertension, Pregnancy-Induced; Inflammation; Interleukin-6; Matrix Metalloproteinase 2; Pre-Eclampsia; Pregnancy; Pregnancy Complications, Cardiovascular; Tissue Plasminogen Activator; Vascular Cell Adhesion Molecule-1

We aimed to compare the serum levels of ET-1, M30, and Angs-1 and -2 in patients with preeclampsia or HELLP syndrome, and normal controls.. In this cross-sectional study of 74 pregnant women, serum levels of ET-1, M30, and Angs-1 and -2 were measured in preeclamptic patients with or without HELLP syndrome. 74 pregnant women; 37 had healthy pregnancies, 25 had preeclampsia (PE), and 12 had HELLP syndrome.. The age, body mass index, gravidity, and parity of patients with normal pregnancy, PE, and HELLP syndrome were comparable (p > 0.05). In HELLP syndrome, compared to healthy or preeclamptic pregnancies, platelet count was lower (p < 0.05) and the values of hepatic function tests were higher (p < 0.05). In HELLP syndrome, ET-1, M30, and Ang-2 were higher compared to healthy or preeclamptic pregnancies (p < 0.05); however, they increased in preeclamptic pregnancies compared to healthy pregnancies though not significant (p > 0.05). In PE or HELLP syndrome, Ang-1 was higher compared to a healthy pregnancy (p < 0.05); however, in HELLP syndrome, it was also higher than in PE though not significant (p > 0.05). We found no significant correlation among these biomarkers and hematological and biochemical parameters (p > 0.05).. For the diagnosis of HELLP syndrome, increased levels of ET-1, M30, and Angs-1 and -2 appear as promising biomarkers after determination of their standardized threshold levels after further studies. As an apoptosis-related biomarker, serum M30 level has a merit to be the most promising test for prediction or differential diagnosis of HELLP syndrome in PE patients.

Topics: Adult; Angiopoietin-1; Angiopoietin-2; Biomarkers; Case-Control Studies; Cross-Sectional Studies; Endothelin-1; Female; Fetal Blood; Gravidity; HELLP Syndrome; Humans; Keratin-18; Parity; Peptide Fragments; Pre-Eclampsia; Pregnancy; Pregnant Women

Deficiency of vitamin D (VD) is associated with preeclampsia (PE), a hypertensive disorder of pregnancy characterized by proinflammatory immune activation. We sought to determine whether VD supplementation would reduce the pathophysiology and hypertension associated with the reduced uterine perfusion pressure (RUPP) rat model of PE. Normal pregnant (NP) and RUPP rats were supplemented with VD2 or VD3 (270 IU and 15 IU/day, respectively) on gestation days 14-18 and mean arterial pressures (MAPs) measured on day 19. MAP increased in RUPP to 123 ± 2 mmHg compared with 102 ± 3 mmHg in NP and decreased to 113 ± 3 mmHg with VD2 and 115 ± 3 mmHg with VD3 in RUPP rats. Circulating CD4+ T cells increased in RUPP to 7.90 ± 1.36% lymphocytes compared with 2.04 ± 0.67% in NP but was lowered to 0.90 ± 0.19% with VD2 and 4.26 ± 1.55% with VD3 in RUPP rats. AT1-AA, measured by chronotropic assay, decreased from 19.5 ± 0.4 bpm in RUPPs to 8.3 ± 0.5 bpm with VD2 and to 15.4 ± 0.7 bpm with VD3. Renal cortex endothelin-1 (ET-1) expression was increased in RUPP rats (11.6 ± 2.1-fold change from NP) and decreased with both VD2 (3.3 ± 1.1-fold) and VD3 (3.1 ± 0.6-fold) supplementation in RUPP rats. Plasma-soluble FMS-like tyrosine kinase-1 (sFlt-1) was also reduced to 74.2 ± 6.6 pg/ml in VD2-treated and 91.0 ± 16.1 pg/ml in VD3-treated RUPP rats compared with 132.7 ± 19.9 pg/ml in RUPP rats. VD treatment reduced CD4+ T cells, AT1-AA, ET-1, sFlt-1, and blood pressure in the RUPP rat model of PE and could be an avenue to improve treatment of hypertension in response to placental ischemia.

Topics: Animals; Arterial Pressure; Birth Weight; CD4-Positive T-Lymphocytes; Dietary Supplements; Endothelin-1; Female; Ischemia; Kidney; Lymphocyte Count; Pre-Eclampsia; Pregnancy; Rats; Receptor, Angiotensin, Type 1; Regional Blood Flow; Uterus; Vascular Endothelial Growth Factor Receptor-1; Vitamin D; Vitamins

Circulating markers for endothelial activation such as endothelin-1 (ET-1), ICAM-1 and VCAM-1 are elevated in women with preeclampsia. Using human umbilical vein endothelial cells (HUVECs) as an in vitro model of the maternal vasculature, we show that activin A and preeclamptic serum upregulate ET-1, ICAM-1, and VCAM-1 in HUVECs. Further, we show that follistatin, a specific binding protein for activin, mitigates the upregulation of ET-1, ICAM-1 and VCAM-1 in HUVECs exposed to either activin A or preeclamptic serum. These data are consistent with activin A contributing to the pathophysiology of preeclampsia and suggest that therapies targeting activin signalling are worth exploring.

Topics: Activins; Adult; Biomarkers; Case-Control Studies; Endothelin-1; Female; Human Umbilical Vein Endothelial Cells; Humans; Intercellular Adhesion Molecule-1; Pre-Eclampsia; Pregnancy; Up-Regulation; Vascular Cell Adhesion Molecule-1

Topics: Adult; Antiphospholipid Syndrome; Arginine; Chronic Disease; Endothelin-1; Endothelium, Vascular; Female; Humans; Hypertension; Pre-Eclampsia; Pregnancy; Prognosis; Thrombosis; Young Adult

Hydroxychloroquine is an anti-malarial drug which, due to its anti-inflammatory and immunomodulatory effects, is widely used for the treatment of autoimmune diseases. In a model of systemic lupus erythematosus hydroxychloroquine has been shown to exert protective endothelial effects. In this study, we aimed to investigate whether hydroxychloroquine was endothelial protective in an in vitro model of TNF-α and preeclamptic serum induced dysfunction. We showed that hydroxychloroquine significantly reduced the production of TNF-α and preeclamptic serum induced endothelin-1 (ET-1). Hydroxychloroquine also significantly mitigated TNF-α induced impairment of angiogenesis. These findings support the further assessment of hydroxychloroquine as an adjuvant therapy in preeclampsia.

Topics: Antimalarials; Endothelin-1; Female; Human Umbilical Vein Endothelial Cells; Humans; Hydroxychloroquine; Neovascularization, Physiologic; Pre-Eclampsia; Pregnancy; Primary Cell Culture; Serum; Tumor Necrosis Factor-alpha

To evaluate whether the maternal, paternal or the combined maternal/paternal contribution of SNP rs5370 of the EDN1 gene is associated with preeclampsia and drove its expression in placenta.. This case-control study included 61 preeclamptic patients and their partners and 49 healthy pregnant women and their partners. The population was sub-divided into three groups: women-only, men-only and combined (women/men). The analysis included genotyping of rs5370 in mothers and fathers and evaluating the expression profile of the EDN1 gene in placenta. Comparisons of categorical variables were performed using chi-square and/or Fisher's exact tests. The intergroup comparisons were analysed with the Mann-Whitney U test. The association between the polymorphism and the disease was evaluated through multivariate regression analysis. Spearman's correlation was performed to test the relationship between pre-gestational history and clinical features of the affected patients with EDN1 gene expression.. The analysis of paternal risk factors associated with preeclampsia revealed no differences between groups. A negative association between SNP rs5370 and preeclampsia was found in men group (OR 0.42; CI 95% 0.18-0.94, p=0.034) but not in women or combined groups. The adjustment for paternal protective factors increased the observed negative association, and the opposite was observed in the presence of paternal risk factors. The expression of the EDN1 gene in the placenta was significantly higher in the group of cases and was not associated with the rs5370 polymorphism.. The paternal rs5370 polymorphism decreases the risk for preeclampsia and is not associated with placental expression of the EDN1 gene.

Topics: Adult; Alleles; Case-Control Studies; Endothelin-1; Female; Gene Expression; Genotype; Humans; Male; Placenta; Polymorphism, Single Nucleotide; Pre-Eclampsia; Pregnancy; Protective Factors; Young Adult

Women with preeclampsia display low renin-angiotensin-aldosterone system activity and a high antiangiogenic state, the latter characterized by high levels of soluble Fms-like tyrosine kinase (sFlt)-1 and reduced placental growth factor levels. To investigate whether renin-angiotensin-aldosterone system suppression in preeclampsia is because of this disturbed angiogenic balance, we measured mean arterial pressure, creatinine, endothelin-1 (ET-1), and renin-angiotensin-aldosterone system components in pregnant women with a high (≥85; n=38) or low (<85; n=65) soluble Fms-like tyrosine kinase-1/placental growth factor ratio. Plasma ET-1 levels were increased in women with a high ratio, whereas their plasma renin activity and plasma concentrations of renin, angiotensinogen, and aldosterone were decreased. Plasma renin activity-aldosterone relationships were identical in both the groups. Multiple regression analysis revealed that plasma renin concentration correlated independently with mean arterial pressure and plasma ET-1. Plasma ET-1 correlated positively with soluble Fms-like tyrosine kinase-1 and negatively with plasma renin concentration, and urinary protein correlated with plasma ET-1 and mean arterial pressure. Despite the lower plasma levels of renin and angiotensinogen in the high-ratio group, their urinary levels of these components were elevated. Correction for albumin revealed that this was because of increased glomerular filtration. Subcutaneous arteries obtained from patients with preeclampsia displayed an enhanced, AT2 receptor-mediated response to angiotensin II. In conclusion, a high antiangiogenic state associates with ET-1 activation, which together with the increased mean arterial pressure may underlie the parallel reductions in renin and aldosterone in preeclampsia. Because ET-1 also was a major determinant of urinary protein, our data reveal a key role for ET-1 in the pathogenesis of preeclampsia. Finally, the enhanced angiotensin responsiveness in preeclampsia involves constrictor AT2 receptors.

Topics: Adult; Angiotensin-Converting Enzyme Inhibitors; Case-Control Studies; Creatinine; Endothelin-1; Female; Humans; Placental Circulation; Pre-Eclampsia; Pregnancy; Pregnancy Outcome; Reference Values; Renin; Renin-Angiotensin System; Risk Assessment

The reduced uterine perfusion pressure (RUPP) rat model of preeclampsia exhibits much of the pathology characterizing this disease, such as hypertension, inflammation, suppressed regulatory T cells (TRegs), reactive oxygen species (ROS), and autoantibodies to the ANG II type I receptor (AT1-AA) during pregnancy. The objective of this study was to determine whether supplementation of normal pregnant (NP) TRegs into RUPP rats would attenuate the pathophysiology associated with preeclampsia during pregnancy. CD4(+)/CD25(+) T cells were isolated from spleens of NP and RUPP rats, cultured, and injected into gestation day (GD) 12 normal pregnant rats that underwent the RUPP procedure on GD 14. On GD 1, mean arterial pressure (MAP) was recorded, and blood and tissues were collected for analysis. One-way ANOVA was used for statistical analysis. MAP increased from 99 ± 2 mmHg in NP (n = 12) to 127 ± 2 mmHg in RUPP (n = 21) but decreased to 118 ± 2 mmHg in RUPP+NP TRegs (n = 17). Circulating IL-6 and IL-10 were not significantly changed, while circulating TNF-α and IL-17 were significantly decreased after supplementation of TRegs. Placental and renal ROS were 339 ± 58.7 and 603 ± 88.1 RLU·min(-1)·mg(-1) in RUPP and significantly decreased to 178 ± 27.8 and 171 ± 55.6 RLU·min(-1)·mg(-1), respectively, in RUPP+NP TRegs; AT1-AA was 17.81 ± 1.1 beats per minute (bpm) in RUPP but was attenuated to 0.50 ± 0.3 bpm with NP TRegs. This study demonstrates that NP TRegs can significantly improve inflammatory mediators, such as IL-17, TNF-α, and AT1-AA, which have been shown to increase blood pressure during pregnancy.

Topics: Adoptive Transfer; Animals; Blood Pressure; Cytokines; Endothelin-1; Female; Gene Expression Regulation; Ischemia; Placenta; Pre-Eclampsia; Pregnancy; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; RNA, Messenger; T-Lymphocytes, Regulatory

To observe the effect of magnesium sulfate, Nifedipine Tablet (NT) combined Salvia Injection (SI) on endothelin-1 (ET-1), nitric oxide (NO), thromboxane A2(TXA2), prostacyclin I2(PG2), and hemorheology of preeclampsia patients.. Totally 704 preeclampsia patients were randomly assigned to the treatment group and the control group, 352 cases in each group. All patients were treated with magnesium sulfate combined NT (on the first day: slow intravenous injection of magnesium sulfate 5 g + intravenous dripping of magnesium sulfate injection 10 g + oral administration of NT 30 mg; on the second and third day, intravenous dripping of magnesium sulfate injection 10 g + oral administration of NT 30 mg), while those in the treatment group were dripped with SI additionally at 20 mL per day for 3 consecutive days. Before and after treatment plasma levels of endothelin-1 (ET-1), nitric oxide (NO), TXA2, PGi2, and hemorheology indicators [such as high blood viscosity (HBV), low blood viscosity (LBV), plasma viscosity (PV), erythrocyte rigidity index (ERI), fibrinogen (FIB)] of two groups were detected.. Compared with the same group before treatment, serum levels of ET-1, TXA2, HBV, LBV, PV, ERI, and FIB decreased in the two groups after treatment (P <0. 05), but levels of NO and PG2 increased (P <0. 05). Compared with the control group in the same period, levels of ET-1, TXA2, HBV, LBV, PV, ERI, and FIB decreased in the treatment group after treatment (P <0. 05), but levels of NO and PGI2 increased (P <0. 05).. Magnesium sulfate, NT combined SI could effectively regulate the balance of ET-1/NO and TXA2/PGI2, and improve hemorheology of preeclampsia patients.

Topics: Drug Therapy, Combination; Drugs, Chinese Herbal; Endothelin-1; Epoprostenol; Female; Hemorheology; Humans; Injections; Magnesium Sulfate; Nifedipine; Nitric Oxide; Pre-Eclampsia; Pregnancy; Salvia; Tablets; Thromboxane A2

To investigate the change of level of serum homocysteine (Hcy), endothelin-1 (ET-1) and nitric oxide (NO) and clinical significance in patients with HDCP.. Two hundred and thirty nine patients with HDCP (137 patients with mild preeclampsia, 102 patients with severe preeclampsia) who were hospitalized between June 2012 and June 2015 and 200 normal pregnancy women in outpatient department were enrolled in our study were divided into HDCP group and control group. Serum Hcy concentration was measured by enzymatic cycling assay. ET-1 concentration was measured by enzyme linked immunosorbent assay. And no concentration was measured by nitrate reductase assay.. Serum Hcy and ET-1 in HDCP group were significantly higher as compared to control group (P<0.05). Level of serum NO in HDCP group was significantly lower than in the control group (P<0.05). Level of serum Hcy and ET-1 in mild and severe preeclampsia group were significantly higher as compared to control group, respectively (P<0.05). Level of serum NO in mild and severe preeclampsia group were significantly lower than in the control group' respectively (P<0.05). Level of serum Hcy and ET-1 in severe preeclampsia group were significantly higher as compared to mild preclampsia group (P<0.05). Level of serum NO in severe preeclampsia group were significantly lower than in mild preeclampsia group (P<0.05). Spearman rank correlation analysis showed that level of serum Hcy and ET-1 was positively correlated with severity of diseases (r=0.689, 0.718, P<0.05). Level of serum NO was negatively correlated with severity of diseases (r=-0.702, P<0.05).. Serum Hcy, ET-1 and NO were associated with pathogenesis of HDCP. Comprehensively measurement of them could effectively evaluate the incidence and progress of HDCP.

Topics: Adult; Biomarkers; Blood Pressure; Case-Control Studies; Endothelin-1; Enzyme-Linked Immunosorbent Assay; Female; Homocysteine; Humans; Nitric Oxide; Pre-Eclampsia; Predictive Value of Tests; Pregnancy; Severity of Illness Index; Young Adult

A history of pre-eclampsia increases the risk of cardiovascular morbidity by mechanisms yet unknown. The aim of the present study was to assess whether plasma norepinephrine (NE) levels are increased 5-6 years after pre-eclamptic pregnancy and to investigate associations with pathophysiological mechanisms of cardiovascular disease: insulin sensitivity, vascular function and arterial pressure. A total of 28 women with previous pre-eclampsia and 20 controls were examined. Blood pressure (BP) and plasma levels of NE and endothelin-1 (ET-1) were measured at rest and after standing for 5 min. Insulin sensitivity was assessed with minimal model analysis and vascular function was assessed using venous occlusion plethysmography and pulse wave analysis. Twenty-four-hour BP measurements were carried out. Women with previous pre-eclampsia had higher levels of NE at rest (P=0.02), which did not associate significantly with insulin sensitivity or overall vasodilatory capacity. The 24-h mean of systolic and diastolic blood pressures (BPs) and heart rate did not differ between the groups (P=0.30, P=0.10 and P=0.46, respectively), and there was no significant association with NE levels. ET-1 levels were similar between the groups, but a positive correlation with systolic (P=0.04) and diastolic (P=0.03) BPs in the upright position was shown in the patient group. Increased levels of plasma NE are sustained in women with previous pre-eclampsia and may contribute to the increased risk for cardiovascular disease in these women.

Topics: Adult; Biomarkers; Blood Pressure; Cardiovascular Diseases; Case-Control Studies; Endothelin-1; Female; Heart Rate; Humans; Hypertension; Insulin Resistance; Norepinephrine; Postpartum Period; Pre-Eclampsia; Pregnancy; Risk Factors; Sympathetic Nervous System; Time Factors

Circulating antiangiogenic factors and proinflammatory cytokines are implicated in the pathogenesis of preeclampsia. This study was performed to test the hypothesis that steroids modify the balance of inflammatory and proangiogenic and antiangiogenic factors that potentially contribute to the patient's evolving clinical state. Seventy singleton women, admitted for antenatal corticosteroid treatment, were enrolled prospectively. The study group consisted of 45 hypertensive women: chronic hypertension (n=6), severe preeclampsia (n=32), and superimposed preeclampsia (n=7). Normotensive women with shortened cervix (<2.5 cm) served as controls (n=25). Maternal blood samples of preeclampsia cases were obtained before steroids and then serially up until delivery. A clinical severity score was designed to clinically monitor disease progression. Serum levels of angiogenic factors (soluble fms-like tyrosine kinase-1 [sFlt-1], placental growth factor [PlGF], soluble endoglin [sEng]), endothelin-1 (ET-1), and proinflammatory markers (IL-6, C-reactive protein [CRP]) were assessed before and after steroids. Soluble IL-2 receptor (sIL-2R) and total immunoglobulins (IgG) were measured as markers of T- and B-cell activation, respectively. Steroid treatment coincided with a transient improvement in clinical manifestations of preeclampsia. A significant decrease in IL-6 and CRP was observed although levels of sIL-2R and IgG remained unchanged. Antenatal corticosteroids did not influence the levels of angiogenic factors but ET-1 levels registered a short-lived increase poststeroids. Although a reduction in specific inflammatory mediators in response to antenatal steroids may account for the transient improvement in clinical signs of preeclampsia, inflammation is unlikely to be the major contributor to severe preeclampsia or useful for therapeutic targeting.

Topics: Adult; Analysis of Variance; Angiogenesis Inducing Agents; Angiogenesis Inhibitors; Betamethasone; Blood Pressure; C-Reactive Protein; Cytokines; Endothelin-1; Female; Glucocorticoids; Humans; Immunoassay; Inflammation Mediators; Injections, Intramuscular; Interleukin-6; Pre-Eclampsia; Pregnancy; Prospective Studies; Severity of Illness Index; Treatment Outcome; Young Adult

To investigate the ability of cardiovascular plasma biomarkers to identify imminent preeclampsia (PE) among pregnant women at triage.. C-terminal pro-arginine vasopressin (copeptin), C-terminal pro-endothelin-1 (CT-proET-1), mid-regional pro-adrenomedullin (MR-proADM), and mid-regional pro-atrial natriuretic peptide (MR-proANP) were prospectively measured in pregnant women presenting at the obstetrical triage units of the University Hospitals of Basel and Zurich, Switzerland. Logistic regression and receiver operating characteristics (ROC) analysis was used to assess and quantify the predictive ability of cardiovascular biomarkers.. Of the 147 included women, 27 (18.4%) were diagnosed at admission with PE. All biomarker levels were significantly higher in participants with PE as compared to controls. However, only MR-proANP, MR-proADM and CT-proET-1 were significant and independent predictors of PE, after taking into account the effect of various clinical confounders. The area under the ROC curve (AUC) was 0.62 (95% confidence interval 0.50-0.73) for copeptin, 0.64 (0.52-0.76) for MR-proADM, 0.71 (0.61-0.82) for CT-proET-1, and 0.83 (0.73-0.92) for MR-proANP. The combination of MR-proANP and MR-proADM resulted in the highest diagnostic performance (AUC 0.88; 0.79-0.96).. Assessment of the cardiovascular plasma biomarkers MR-proANP and MR-proADM holds promise to support diagnosis of PE at triage.

Topics: Adrenomedullin; Adult; Atrial Natriuretic Factor; Biomarkers; Cardiovascular Diseases; Endothelin-1; Epidemiologic Studies; Female; Glycopeptides; Humans; Peptide Fragments; Pre-Eclampsia; Pregnancy; Protein Precursors; Triage

Preeclampsia is a human pregnancy-specific disorder characterized by a placental pro-inflammatory response in combination with an imbalance of angiogenic factors and clinical symptoms, including hypertension and proteinuria. Insufficient uteroplacental oxygenation in preeclampsia due to impaired trophoblast invasion during placentation is believed to be responsible for many of the molecular events leading to the clinical manifestations of this disease. We investigated the use of hypoxic treatment of the dual placental perfusion system as a model for preeclampsia. A modified perfusion technique allowed us to achieve a mean soluble oxygen tension within the intervillous space (IVS) of 5-7% for normoxia and <3% for hypoxia (as a model for preeclampsia). We assayed for the levels of different inflammatory cytokines, oxidative stress markers, as well as other factors, such as endothelin (ET)-1 that are known to be implicated as part of the inflammatory response in preeclampsia. Our results show a significant increase under hypoxia in the levels of different inflammatory cytokines, including IL-6 (P=0.002), IL-8 (P<0.0001), TNF-α (P=0.032) and IFN-γ (P=0.009) at 360 min in maternal venous samples (n=6). There was also a significant increase in ET-1 levels under hypoxia both on the maternal side at 30 min (P=0.003) and fetal side at 360 min (P=0.036) (n=6). Other markers of oxidative stress, including malondialdehyde and 8-iso-protaglandin F2α (P=0.009) also show increased levels. Overall, these findings indicate that exposure of ex vivo dually perfused placental tissue to hypoxia provides a useful model for mimicking the inflammatory response characteristic of preeclampsia. This would therefore provide a powerful tool for studying and further delineating the molecular mechanisms involved in the underlying pathophysiology of preeclampsia.

Topics: Biomarkers; Cell Hypoxia; Cytokines; Dinoprost; Endothelin-1; Female; Humans; In Vitro Techniques; Kinetics; Lipid Peroxidation; Malondialdehyde; Oxidative Stress; Perfusion; Placenta; Pre-Eclampsia; Pregnancy; Up-Regulation

Preeclampsia (PE) is associated with hypertension and elevated endothelin (ET-1), an indicator of endothelial cell activation and dysfunction. Reduction of uteroplacental perfusion (RUPP) in the pregnant rat model of PE is characterized by elevated mean arterial pressure, inflammatory cytokines, and activation of the ET-1 system. We aim to determine whether 17-alpha-hydroxyprogesterone caproate (17-OHPC) or progesterone suppresses these pathways.. Plasma progesterone was purified from normal pregnant (NP) and PE patients and measured via enzyme-linked immunosorbent assay. Human umbilical vein endothelial cells were exposed to the sera with or without progesterone added and ET-1 was measured. Pregnant rats underwent the RUPP procedure with or without intraperitoneal 17-OHPC. Mean arterial pressure was compared in RUPP vs NP rats. Human umbilical vein endothelial cells were exposed to NP or RUPP sera, with and without progesterone and ET-1 measured.. Progesterone was significantly decreased in PE women compared with NP women. In response to human sera, ET-1 was elevated in PE women compared to NP women, and decreased with addition of progesterone. Mean arterial pressure was significantly elevated in RUPP vs NP rats but was attenuated by 17-OHPC. ET-1 secretion was stimulated significantly by RUPP compared to NP rat sera, but attenuated by progesterone.. Circulating progesterone is significantly lower in PE women compared to controls. 17-OHPC attenuates hypertension in response to placental ischemia in RUPP rats. Progesterone blunts vascular ET-1 stimulated at cellular level by sera from PE women or RUPP rats. Decreased circulating progesterone is associated with stimulation of ET-1. 17-OHPC supplementation blunts hypertension and progesterone blunts endothelial cell ET-1 secretion in response to placental ischemia.

Topics: 17 alpha-Hydroxyprogesterone Caproate; Animals; Disease Models, Animal; Endothelial Cells; Endothelin-1; Enzyme-Linked Immunosorbent Assay; Female; Humans; Hydroxyprogesterones; Hypertension; Ischemia; Placenta; Placental Circulation; Pre-Eclampsia; Pregnancy; Progesterone; Progestins; Rats; Rats, Sprague-Dawley

The aim of the study was to estimate the levels of vascular endothelial growth factor (VEGF) and endothelin-1 (ET-1) in maternal serum from normal pregnant women and women with pre-eclampsia. Serum concentrations of VEGF and ET-1 were measured in maternal blood in control group (n = 40) and in pregnancies complicated by pre-eclampsia (n = 40). Results showed that maternal VEGF levels were significantly raised in women with pre-eclampsia (p < 0.001). ET-1 concentration was not significantly different among women with pre-eclampsia compared with that in the control group. It was concluded that an increase in serum VEGF level was demonstrated in pre-eclampsia, suggesting that VEGF is involved in pathogenesis of pre-eclampsia. Further studies are needed to determine the serum concentrations of VEGF in pregnant women before the development of pre-eclampsia.

Topics: Adult; Biomarkers; Case-Control Studies; Endothelin-1; Female; Humans; Pre-Eclampsia; Pregnancy; Vascular Endothelial Growth Factor A; Young Adult

Preeclampsia is a life-threatening pregnancy disorder. However, its pathogenesis remains unclear. We tested the hypothesis that gestational hypoxia induces preeclampsia-like symptoms via heightened endothelin-1 (ET-1) signaling. Time-dated pregnant and nonpregnant rats were divided into normoxic and hypoxic (10.5% O2 from the gestational day 6-21) groups. Chronic hypoxia had no significant effect on blood pressure or proteinuria in nonpregnant rats but significantly increased blood pressure on day 12 (systolic blood pressure, 111.7 ± 6.1 versus 138.5 ± 3.5 mm Hg; P=0.004) and day 20 (systolic blood pressure, 103.4 ± 4.6 versus 125.1 ± 6.1 mm Hg; P=0.02) in pregnant rats and urine protein (μg/μL)/creatinine (nmol/μL) ratio on day 20 (0.10 ± 0.01 versus 0.20 ± 0.04; P=0.04), as compared with the normoxic control group. This was accompanied with asymmetrical fetal growth restriction. Hypoxia resulted in impaired trophoblast invasion and uteroplacental vascular remodeling. In addition, plasma ET-1 levels, as well as the abundance of prepro-ET-1 mRNA, ET-1 type A receptor and angiotensin II type 1 receptor protein in the kidney and placenta were significantly increased in the chronic hypoxic group, as compared with the control animals. Treatment with the ET-1 type A receptor antagonist, BQ123, during the course of hypoxia exposure significantly attenuated the hypoxia-induced hypertension and other preeclampsia-like features. The results demonstrate that chronic hypoxia during gestation induces preeclamptic symptoms in pregnant rats via heightened ET-1 and ET-1 type A receptor-mediated signaling, providing a molecular mechanism linking gestational hypoxia and increased risk of preeclampsia.

Topics: Animals; Blood Pressure; Disease Models, Animal; Endothelin A Receptor Antagonists; Endothelin-1; Female; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit; Kidney; Peptides, Cyclic; Placenta; Pre-Eclampsia; Pregnancy; Proteinuria; Rats; Rats, Sprague-Dawley; Receptor, Angiotensin, Type 1; Signal Transduction

To explore the protective effects of danshen (Salvia Miltiorrhiza) on vascular endothelial cells in hypertension patients in the gestation period.. The umbilical vein endothelial cells pre-incubated with Danshen solution at different concentrations (0, 100, 200, and 300 mg/L) were randomly divided into 3 groups, i.e., the blank control group (8 cases), the normal control group (14 cases, cultured in the serum from 14 normal pregnant women), and the observation group (14 cases, cultured in the serum from 14 pregnant women with severe pre-eclampsia). The levels of nitric oxide (NO) and endothelin-1 (ET-1) in each culture supernatant were detected respectively.. The ET-1 level was higher in 300 mg/L Danshen solution group than in 0 mg/L and 100 mg/L Danshen solution groups (P <0.05). The NO level was lower in the observation group than in the blank control group and the normal control group (P <0. 05). The NO level was higher in 200 mg/L Danshen solution group than in 0 mg/L Danshen solution group (P <0.05). The NO level was higher in 300 mg/L Danshen solution group than in 0 mg/L, 100 mg/L, and 200 mg/L Danshen solution groups (P <0.05).. Danshen could increase the secretion of NO from in vitro umbilical vein endothelial cells cultured in the serum from patients with pre-eclampsia, and reduce the secretion of ET-1.

Topics: Cells, Cultured; Culture Media; Drugs, Chinese Herbal; Endothelial Cells; Endothelin-1; Female; Humans; Nitric Oxide; Phenanthrolines; Pre-Eclampsia; Pregnancy; Salvia miltiorrhiza; Serum; Umbilical Veins

Hypertension during preeclampsia is associated with increased maternal vascular sensitivity to angiotensin II (ANGII). This study was designed to determine mechanisms whereby agonistic autoantibodies to the ANGII type I receptor (AT1-AA) enhance blood pressure (mean arterial pressure [MAP]) and renal vascular sensitivity to ANGII during pregnancy. First, we examined MAP and renal artery resistance index in response to chronic administration of ANGII or AT1-AA or AT1-AA+ANGII in pregnant rats compared with control pregnant rats. To examine mechanisms of heightened sensitivity in response to AT1-AA during pregnancy, we examined the role of endogenous ANGII in AT1-AA-infused pregnant rats, and that of endothelin-1 and oxidative stress in AT1-AA+ANGII-treated rats. Chronic ANGII increased MAP from 95±2 in normal pregnant rats to 115±2 mm Hg; chronic AT1-AA increased MAP to 118±1 mm Hg in normal pregnant rats, which further increased to 123±2 mm Hg with AT1-AA+ANGII. Increasing ANGII from 10(-11) to 10(-8) decreased afferent arteriole diameter from 15% to 20% but sharply decreased afferent arteriole diameter to 60% in AT1-AA-pretreated vessels. Renal artery resistance index increased from 0.67 in normal pregnant rats to 0.70 with AT1-AA infusion, which was exacerbated to 0.74 in AT1-AA+ANGII-infused rats. AT1-AA-induced hypertension decreased with enalapril but was not attenuated. Both tissue endothelin-1 and reactive oxygen species increased with AT1-AA+ANGII compared with AT1-AA alone, and blockade of either of these pathways had significant effects on MAP or renal artery resistance index. These data support the hypothesis that AT1-AA, via activation of endothelin-1 and oxidative stress and interaction with endogenous ANGII, is an important mechanism whereby MAP and renal vascular responses are enhanced during preeclampsia.

Topics: Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Aorta; Autoantibodies; Blood Pressure; Enalapril; Endothelin-1; Female; Hypertension, Pregnancy-Induced; Kidney; Oxidative Stress; Placenta; Pre-Eclampsia; Pregnancy; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; Receptor, Angiotensin, Type 1

Preeclampsia is a leading cause of maternal and fetal morbidity/mortality; however, the pathophysiological mechanisms are unclear. Vascular endothelial dysfunction in preeclampsia has been partially attributed to changes in endothelin-1 (ET-1). Several enzymes, including matrix metalloproteinases (MMPs; particularly MMP-2), cleave the inactive precursor big ET-1 (bET-1) to active ET-1. Notably, expression levels of MMP-2 have been shown to be on the increase in women who subsequently develop preeclampsia. We hypothesized that the increased MMP-2 expression leads to increased bET-1 conversion, thereby increasing vasoconstriction in preeclampsia. A reduced uteroplacental perfusion pressure (RUPP) model of preeclampsia in the rat was used to assess mesenteric artery vascular function. Responses to bET-1 (3-310 nmol/L) and ET-1 (1-200 nmol/L) were studied in the presence or absence of inhibitors of enzymes known to cleave bET-1. Vascular contractility in response to bET-1 was greater in RUPP than Sham (P<0.001), whereas neither responses to ET-1 nor maximal contractility to high potassium salt solution (123.70 mmol/L) were different. MMP inhibition with GM6001 (30 μmol/L) significantly decreased responses to bET-1 in RUPP (P<0.001) but not Sham-operated rats. Interestingly, combined treatment with GM6001 and L-NG-nitroarginine methyl ester (100 μmol/L) revealed a NO modulation of MMPs that was reduced in RUPP. In summary, we found increased vascular contractility to bET-1 in the RUPP model of preeclampsia that was likely attributable to upstream enzymatic pathways. These data are consistent with a greater contribution of MMP to cleavage of bET-1 to ET-1 ex vivo in RUPP, suggesting that this enzyme may be partially responsible for increased bET-1-induced contractility.

Topics: Animals; Dipeptides; Endothelin-1; Female; Hemodynamics; Matrix Metalloproteinase 2; Mesenteric Arteries; Mesentery; Nitric Oxide; Pre-Eclampsia; Pregnancy; Protease Inhibitors; Rats; Rats, Sprague-Dawley; Uterus; Vasoconstriction

Placental overproduction of anti-angiogenic soluble fms-like tyrosine kinase-1 (sFlt-1) and soluble endoglin (sEng) has a key role in the development of preeclampsia (PE). Circulating endothelin-1 (ET-1) levels are also elevated in PE. In this study, we investigated the correlation between ET-1 and sFlt-1, placental growth factor (PlGF), sEng levels during uncomplicated normotensive pregnancy and PE. A total of 218 pregnant primigravid women were enrolled: 110 with PE and 108 uncomplicated normotensive pregnancies. PE was defined as new onset of elevated blood pressure (BP) >140/90 mm Hg and ≥2+ proteinuria on two occasions after 20 weeks of gestation in previously normotensive pregnant women. Circulating ET-1, sFlt-1, sEng and PlGF levels were estimated using enzyme immunoassays, and correlation between variables was ascertained. Women with PE showed higher levels of sFlt-1 (41.5±15.7 vs 6.15±3.4 ng ml(-1), P<0.001), sEng (84.9±38.8 vs 13.2±6.3 ng ml(-1), P<0.001), ET-1 (1.52±0.55 vs 0.88±0.35 pg ml(-1), P<0.001) and sFlt-1:PlGF ratio (591.1±468.4 vs 18.3±2.1, P<0.001); and lower levels of PlGF (96.3±47.2 vs 497.6±328.2 pg ml(-1), P<0.001). BP levels showed an independent relationship with sFlt-1:PlGF ratio in normotensive pregnant women and with sFlt-1:PlGF ratio and ET-1 in PE. sFlt-1 and sFlt-1:PlGF ratio correlated with proteinuria. ET-1 correlated significantly with sFlt-1, sEng and sFlt-1:PlGF ratio in PE. Our results show an association between elevation of sFlt-1 and sEng and ET-1 in the maternal circulation in PE, and strengthen the possibility that ET-1 may be a mediator in genesis of PE syndrome secondary to anti-angiogenic factors released by the placenta.

Topics: Adult; Antigens, CD; Biomarkers; Case-Control Studies; Endoglin; Endothelin-1; Female; Humans; Hypertension; Placenta Growth Factor; Pre-Eclampsia; Pregnancy; Pregnancy Complications; Pregnancy Proteins; Receptors, Cell Surface; Signal Transduction; Vascular Endothelial Growth Factor Receptor-1

In very preterm infants, clinical decision-making, such as closing a patent ductus arteriosus (PDA), may be aided by measuring circulating natriuretic and endothelial pro-peptides.. To investigate the association between perinatal characteristics, PDA echocardiography and plasma concentrations of stable pro-peptides of B-type natriuretic peptide (NT-proBNP), atrial natriuretic peptide (MR-proANP) and endothelin-1 (CT-proET-1).. A prospective, cross-sectional, single-center study was performed in 66 infants who were less than 32 weeks of gestational age. Pro-peptide concentrations were determined at birth and at day 2-3 of life.. Plasma concentrations of all 3 pro-peptides increased on average 2- to 5-fold from birth to day 2-3 of life. NT-proBNP and MR-proANP were closely related at birth and at day 2-3 (Rs 0.902 and 0.897, respectively, p < 0.001), whereas CT-proET-1 was related to NT-proBNP and MR-proANP at birth (Rs 0.478 and 0.460, respectively, p < 0.001) but not at day 2-3. Birth weight was negatively related to all 3 pro-peptides at birth (p < 0.01); however, preeclampsia and compromised placental perfusion were associated with elevated NT-proBNP and MR-proANP concentrations at birth. At day 2-3, MR-proANP and NT-proBNP correlated significantly with the ductal diameter (Rs 0.416 and 0.415, respectively, both p = 0.011), whereas CT-proET-1 correlated with the left atrium/aorta ratio (Rs 0.506, p = 0.027). CT-proET-1 was elevated in infants with treated compared to untreated PDA [median (5-95% range) 388 (272-723) vs. 303 (152-422) pmol/l, p = 0.011], but not NT-proBNP or MR-proANP.. CT-proET-1 is a promising predictor in determining the need for PDA intervention.

Topics: Atrial Natriuretic Factor; Ductus Arteriosus, Patent; Echocardiography; Endothelin-1; Female; Humans; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Male; Natriuretic Peptide, Brain; Peptide Fragments; Placenta; Pre-Eclampsia; Pregnancy; Protein Precursors

Preeclampsia remains a major health concern in the United States and worldwide. Recent research has begun to shed light on the underlying mechanisms responsible for the symptoms of preeclampsia, and may provide new avenues for therapy for the preeclamptic patient.. The central role of placental ischemia in the manifestation of preeclampsia has provided new understanding for the origin of pathogenic factors in the preeclamptic patient. The release of soluble factors into the maternal bloodstream from the ischemic placenta is now recognized as a central mechanism in disease manifestation. Specifically, the importance of the vascular endothelial growth factor antagonist soluble fms-like tyrosine kinase and immune factors as factors regulating maternal endothelial dysfunction has become widely acknowledged. Furthermore, mounting evidence implicates the signaling protein endothelin-1 as the final converging factor in the multifaceted cascades that are responsible for the symptomatic manifestation of preeclampsia. Endothelin-1, as a final common pathway in the pathogenic cascade of preeclampsia, presents an intriguing new therapeutic approach for preeclamptic patients.. Identification of antiangiogenic, autoimmune, and inflammatory factors produced in response to placental ischemia have provided potential new avenues for future research into novel therapies for the preeclamptic patient, and suggest new therapeutic avenues for the treatment of preeclampsia.

Topics: Adaptive Immunity; Angiogenesis Inhibitors; Endothelin-1; Female; Humans; Immunity, Innate; Ischemia; Placenta; Pre-Eclampsia; Pregnancy; Signal Transduction; Vascular Endothelial Growth Factor Receptor-1

Excess soluble fms-like tyrosine kinase 1 (sFlt-1) of vascular endothelial growth factor receptor 1 secreted from the placenta causes pre-eclampsia-like features by antagonizing vascular endothelial growth factor signaling, which can lead to reduced endothelial nitric oxide synthase (eNOS) activity; the effect of this concomitant decrease in eNOS activity is unknown. We tested whether the decrease in nitric oxide occurring in female mice lacking eNOS aggravates the pre-eclampsia-like phenotype induced by increased sFlt-1. Untreated eNOS-deficient female mice had higher BP than wild-type mice. Adenovirus-mediated overexpression of sFlt-1 increased systolic BP by approximately 27 mmHg and led to severe loss of fenestration of glomerular capillary endothelial cells in both eNOS-deficient and wild-type mice. However, only the eNOS-deficient sFlt-1 mice exhibited severe foot process effacement. Compared with wild-type sFlt-1 mice, eNOS-deficient sFlt-1 mice also showed markedly higher urinary albumin excretion (467±74 versus 174±23 μg/d), lower creatinine clearance (126±29 versus 452±63 μl/min), and more severe endotheliosis. Expression of preproendothelin-1 (ET-1) and its ET(A) receptor in the kidney was higher in eNOS-deficient sFlt-1 mice than in wild-type sFlt-1 mice. Furthermore, the selective ET(A) receptor antagonist ambrisentan attenuated the increases in BP and urinary albumin excretion and ameliorated endotheliosis in both wild-type and eNOS-deficient sFlt-1 mice. Ambrisentan improved creatinine clearance and podocyte effacement in eNOS-deficient sFlt-1 mice. In conclusion, reduced maternal eNOS/nitric oxide exacerbates the sFlt1-related pre-eclampsia-like phenotype through activation of the endothelin system.

Topics: Albuminuria; Animals; Disease Models, Animal; Endothelin-1; Female; Glomerular Filtration Rate; Mice; Mice, Inbred C57BL; Nitric Oxide Synthase Type III; Phenotype; Phenylpropionates; Placenta; Pre-Eclampsia; Pregnancy; Pregnancy, Animal; Pyridazines; Random Allocation; Receptors, Endothelin; Sensitivity and Specificity; Vascular Endothelial Growth Factor Receptor-1

Recent evidence implicates placental endoplasmic reticulum (ER) stress in the pathophysiological characteristics of preeclampsia. Herein, we investigate whether endothelin (ET)-1, which induces Ca(2+) release from the ER, can induce placental ER stress. Loss of ER Ca(2+) homeostasis impairs post-translational modification of proteins, triggering ER stress-response pathways. IHC confirmed the presence of both ET-1 and its receptors in the syncytiotrophoblast. Protein levels and immunoreactivity of ET-1 and the endothelin B receptor (ETBR) were increased in preeclamptic samples compared with normotensive controls. JEG-3 and BeWo choriocarcinoma cells treated with ET-1 displayed an increase in ER stress markers. ET-1 induced phospho-activation of the ETBR. Treating cells with BQ788, an ETBR antagonist, or small-interfering RNA knockdown of the receptor inhibited induction of ER stress. ET-1 also stimulated p-phospholipase C (PLC)γ1 levels. By using inhibitors of PLC activation, U73122, and the inositol 1,4,5-triphosphate (IP(3)) receptor, xestospongin-C, we demonstrated that ET-1 induces ER stress via the PLC-IP(3) pathway. Furthermore, ET-1 levels increased in the syncytiotrophoblast of explants from normal placentas after hypoxia-reoxygenation in vitro. Conditioned medium from hypoxia-reoxygenation explants also contained higher ET-1 levels, which induced ER stress in JEG-3 cells that was abolished by an ET-1-neutralizing antibody. Collectively, the data show that ET-1 induced ER stress in trophoblasts via the ETBR and initiation of signaling through the PLC-IP(3) pathway, with the potential for autocrine stimulation.

Topics: Dose-Response Relationship, Drug; Endoplasmic Reticulum Stress; Endothelin-1; Female; Gene Knockdown Techniques; Humans; Inositol 1,4,5-Trisphosphate Receptors; Phosphorylation; Placenta; Pre-Eclampsia; Pregnancy; Receptor, Endothelin A; Receptor, Endothelin B; RNA, Small Interfering; Signal Transduction; Tissue Culture Techniques; Trophoblasts; Tumor Cells, Cultured; Type C Phospholipases

Topics: Animals; Autoantibodies; Blood Pressure; Disease Models, Animal; Endothelin-1; Female; Humans; Hypertension; Ischemia; Placenta; Pre-Eclampsia; Pregnancy; Rats; Receptor, Angiotensin, Type 1; Tumor Necrosis Factor-alpha; Vascular Endothelial Growth Factor Receptor-1

Preeclampsia (PE), fetal growth restriction (FGR) and gestational diabetes mellitus (GDM) are major pregnancy complications affecting maternal and fetal health. The placenta and the vasoconstrictor endothelin-1 (ET-1) have a controlling and mediating role in these conditions. This study tested the hypothesis that the expression of ET-1 and its receptors (ET(A) and ET(B)) is altered in these pathologies and differs between early (gestational week [GW] ≤ 34) and late (GW > 34) third trimester pregnancies.. The study included 88 women (GW 28-41) with PE (blood pressure >140/90 mmHg, protein >300 mg/24 hrs; n=14), FGR (<10th birthweight centile and pathological umbilical blood flow; n=13), PE+FGR (n=5) and GDM (n=21), and gestational age-matched controls (n=35). ET-1, ET(A) and ET(B) mRNA and ET(A) and ET(B) protein were quantified in placental tissues by real-time PCR and immunoblotting.. The ET/ETR mRNA system is altered in PE and PE+FGR and GDM. Expression of ET-1, ET(A) and ET(B) is upregulated in early onset PE and PE+FGR with stronger effect in PE+FGR. GDM down regulated ET/ETR mRNA in the placentas in late third trimester of pregnancy. ET/ETR protein is virtually unchanged.. Early onset PE (≤GW34) with or without FGR is associated with increased mRNA expression of the ET/ETR system, while in late onset PE and GDM the opposite effect was observed. This study supports the emerging concept that early and late onset PE are different diseases.

Topics: Adult; Case-Control Studies; Diabetes, Gestational; Down-Regulation; Endothelin-1; Female; Fetal Growth Retardation; Gestational Age; Humans; Placenta; Polymerase Chain Reaction; Pre-Eclampsia; Pregnancy; Pregnancy Trimester, Third; Receptor, Endothelin A; Receptor, Endothelin B; RNA, Messenger; Up-Regulation; Young Adult

Low molecular weight heparin (LMWH) has been used to treat certain kidney diseases such as pre-eclampsia, in which extensive levels of proteinuria are associated with dysfunction of glomerular endothelium. In our study, we investigated whether LMWH could affect the permeability of and ET-1 expression in human glomerular endothelial cells (GEnC) incubated with pre-eclampsia serum.. Serum from pre-eclampsia patients was collected and incubated with GEnC in the absence or presence of LMWH. We assessed the permeability of glomerular endothelial monolayer by measuring the amount of bovine serum albumin (BSA) that crosses into the lower chamber of a trans-well device. In addition, we measured ET-1 mRNA expression levels in and proliferation and apoptotic rates of GEnC exposed to pre-eclampsia serum with or without LMWH.. The permeability of ET-1 mRNA expression in GEnC increased upon incubation with pre-eclampsia serum, but decreased significantly when LMWH was added. The presence of LMWH did not alter the proliferation and apoptosis of GEnC incubated with pre-eclampsia serum.. Low molecular weight heparin maintains the integrity of the kidney probably by strengthening the defence of glomerular endothelium.

Topics: Adult; Apoptosis; Capillary Permeability; Cell Line; Cell Proliferation; Endothelial Cells; Endothelin-1; Female; Heparin, Low-Molecular-Weight; Humans; Kidney Glomerulus; Pre-Eclampsia; Pregnancy; RNA, Messenger; Serum; Serum Albumin, Bovine; Time Factors

To investigate the expression of autoantibodies to the angiotensin II type I receptor (AT1-AA) and endothelin-1 (ET-1) in pregnant women's blood and explore their correlation with the pathogenesis of preeclampsia.. Ninety pregnant women who delivered from June 2011 to December 2011 in the First Affiliated Hospital of Zhengzhou University were chosen as the study objects. They were divided into mild preeclampsia group (n = 30), severe preeclampsia group (n = 30) and normal group (control group, n = 30). The levels of AT1-AA and ET1 in maternal peripheral blood and umbilical cord blood were detected by ELISA, and the mRNA expression levels of AT1-AA and ET1 in placenta tissues were determined by reverse transcription (RT) PCR. Moreover, the correlation clinical indexes were detected and analysed.. (1) The levels of AT1-AA and ET1 in maternal peripheral blood of preeclampsia [mild group: (114 ± 19) ng/L and (31 ± 9) ng/L, severe group: (145 ± 15) ng/L and (38 ± 10) ng/L] were both significantly higher than that of control group [(59 ± 5) ng/L, (17 ± 4) ng/L]. In addition, compared with mild group, the levels of AT1-AA and ET1 in severe group were significantly higher (P < 0.05). (2) The levels of AT1-AA and ET1 in umbilical cord blood of preeclampsia [mild group: (105 ± 14) ng/L and (35 ± 6) ng/L, severe group: (118 ± 14) ng/L and (40 ± 5) ng/L] were significantly higher than that of control group [(61 ± 12) ng/L, (24 ± 5) ng/L]. In addition, compared with mild group, the levels of AT1-AA and ET1 in severe group were significantly higher (P < 0.05). (3) The mRNA expression levels of AT1-AA and ET1 in placenta tissues of mild group (0.313 ± 0.039, 0.296 ± 0.028) and severe group (0.568 ± 0.052, 0.577 ± 0.046) were significantly higher than that in control group (0.198 ± 0.017, 0.137 ± 0.012), and the levels in severe group were significantly higher than that in mild group (P < 0.05). (4) There was an evident positive correlation between AT1-AA and ET1 levels of preeclampsia women's peripheral blood, umbilical cord blood and placenta (P < 0.05). (5) The level of AT1-AA in umbilical cord blood of preeclampsia pregnant women was positively correlated with S/D value of umbilical artery (P < 0.05), and negatively correlated with the weight of the birth and the placental (P < 0.05).. The AT1-AA in the blood of pregnant women plays an important role in promoting the generation and development of preeclampsia by increasing the ET1 secretion.

Topics: Adult; Autoantibodies; Case-Control Studies; Endothelin-1; Female; Fetal Blood; Humans; Hypertension, Pregnancy-Induced; Infant, Newborn; Placenta; Pre-Eclampsia; Pregnancy; Receptor, Angiotensin, Type 1; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Severity of Illness Index

Pre-eclampsia is new onset hypertension during pregnancy with proteinuria. The initiating event in pre-eclampsia is postulated to involve reduced placental perfusion, which leads to widespread dysfunction of the maternal vascular endothelium. Cytokines also appear to contribute to the development of the pathological condition. The aim of this study was to evaluate the role of cytokines in pre-eclampsia and to study the relationship between endothelin-1 and cytokines with the severity of the disease.. This cross-sectional study included 300 women with pre-eclampsia and 200 healthy pregnant women. Their blood samples were analyzed for endothelin-1 and inflammatory cytokines.. Increased endothelin-1 and cytokines [tumor necrosis factor-α, interleukin-2 (IL-2) and γ-interferon (IFN-γ)] levels were found in pre-eclampsia (P < 0.001). Significant positive correlation was seen between endothelin-1 and cytokine level (IL-2 and IFNγ) in the pre-eclamptic group (P = 0.001).. We conclude that pre-eclampsia is associated with increased levels of both endothelin-1 and circulating inflammatory cytokines, which points toward the role of endothelial and inflammatory components.

Topics: Adult; Cross-Sectional Studies; Cytokines; Endothelin-1; Enzyme-Linked Immunosorbent Assay; Female; Humans; India; Inflammation; Interferon-gamma; Interleukin-2; Pilot Projects; Pre-Eclampsia; Pregnancy; Tumor Necrosis Factor-alpha

Preeclampsia (PE) is a life-threatening hypertensive disorder of pregnancy. Elevated circulating endothelin-1 (ET-1) is associated with the disease. However the molecular basis of increased ET-1 production and its role in PE are unknown. This study aimed to investigate the causative factors, pathological role of elevated ET-1 production in PE, and the underlying mechanisms. In this study, we found that IgG from women with PE, in contrast to IgG from normotensive pregnant women, induced preproET-1 mRNA expression via angiotensin II type 1 receptor activation in kidneys and placentas in pregnant mice. The ET-A receptor-specific antagonist BQ123 significantly attenuated autoantibody-induced hypertension, proteinuria, and renal damage in pregnant mice, demonstrating that autoantibody-induced ET-1 production contributes to pathophysiology. Mechanistically, we discovered that IL-6 functioned downstream of TNF-α signaling, contributing to increased ET-1 production in pregnant mice. IL-6 blockade inhibited preeclamptic features in autoantibody-injected pregnant mice. Extending the data to human studies, we found that IL-6 was a key cytokine underlying ET-1 induction mediated by IgG from women with PE in human placental villous explants and that endothelial cells are a key source of ET-1. Overall, we provide human and mouse studies showing that angiotensin II type I receptor-agonistic autoantibody is a novel causative factor responsible for elevated ET-1 production and that increased TNF-α/IL-6 signaling is a key mechanism underlying increased ET-1 production and subsequent maternal features. Significantly, our findings revealed novel factors and signaling cascades involved in ET-1 production, subsequent disease symptom development, and possible therapeutic intervention in the management of PE.

Topics: Animals; Autoantibodies; Disease Models, Animal; Endothelin-1; Female; Humans; Immunoglobulin G; Interleukin-6; Kidney; Mice; Placenta; Pre-Eclampsia; Pregnancy; Receptor, Angiotensin, Type 1; RNA, Messenger; Signal Transduction; Tumor Necrosis Factor-alpha

Recently much attention has been focused on endothelin-1 (ET-1) and endothelin-1 converting enzyme (ECE-1) gene polymorphisms and connected changes in ET-1 concentration. Additionally these processes have been shown to be possibly involved in preeclampsia susceptibility. The aim of this study was to evaluate the correlation between ET-1 (Lys198Asn) and ECE-1 (Thr341lle) gene polymorphisms and the risk of gestational hypertension and preeclampsia.. The study group consisted of 110 hypertensive (69 with gestational hypertension and 41 preeclamptic) pregnant women. The control group included 150 healthy pregnant women. The frequency of investigated polymorphisms was examined by polymerase chain reaction and restriction fragment length polymorphism (PCR/RFLP) assay. There were no statistically significant differences in genotype frequencies of ET-1 Lys198Asn and ECE-1 Thr341lle gene polymorphic variants between hypertensive pregnant women and the control group. There were also no remarkable differences between GH and PE groups when compared to the controls. However parallel presence of both Thr341lle ECE-1 and Lys198Asn ET-1 variant localisation showed a higher occurrence rate of ECE-1 CT/ET-1 GT heterozygotic genotypes in the control group (5,3%) than in the whole study or GH and PE groups (0.9%, 1.4% and 0.0% respectively p = ns). In preeclamptic women, the higher systolic blood pressure value was observed in GG Lys198Asn ET-1 genotype carriers (180.7 mmHg) than in patients with at least one mutated T allele (GT and TT) (167.3 mmHg, p = ns). The lowest blood pressure level was connected with the mutated TT Lys198Asn ET- 1 genotype presence.. Results of this study suggest lack of direct correlation of Lys198Asn ET-1 and Thr341lle ECE-1 gene polymorphisms with risk of gestational hypertension and preeclampsia in the studied population of Polish women. High prevalence of ECE-1 CT/ET-1 GT heterozygote genotypes of both Thr341lle ECE-1 and Lys198Asn ET-1 polymorphisms in healthy pregnant subjects compared to GH and PE groups suggests the protective role of mutated alleles in the development of PE. The carrier of mutated TT genotype of Lys198Asn ET-1 polymorphism is probably connected with lower systolic blood pressure level in preeclamptic women. Future studies are needed to establish the role of analysed polymorphisms in the etiology of gestational hypertension and preeclampsia.

Topics: Adult; Aspartic Acid Endopeptidases; Case-Control Studies; Endothelin-1; Endothelin-Converting Enzymes; Female; Heterozygote; Humans; Hypertension, Pregnancy-Induced; Metalloendopeptidases; Poland; Polymorphism, Restriction Fragment Length; Pre-Eclampsia; Pregnancy; Reference Values; Young Adult

Preeclampsia (PE) is one of the leading causes of fetal and maternal morbidity, affecting 5-10% of all pregnancies, and lacks an effective treatment. The exact etiology of the disorder is unclear, but placental ischemia has been shown to be a central causative agent. In response to placental ischemia, the antiangiogenic protein fms-like tyrosine kinase-1 (sFlt-1), a VEGF antagonist, and reactive oxygen species are secreted, leading to the maternal syndrome. One promising therapeutic approach to treat PE is through manipulation of the heme oxygenase-1 (HO-1) protein. It has been previously reported that HO-1 and carbon monoxide downregulate sFlt-1 production in vitro, and we have recently shown that HO-1 induction significantly attenuates placental ischemia-induced hypertension, partially through normalization of the sFlt-1-to-VEGF ratio in the placenta. The purpose of this study was to determine whether HO-1 induction would have beneficial effects independently of sFlt-1 suppression. To that end, pregnant rats were continuously infused with recombinant sFlt-1 from gestational days 14-19, and circulating sFlt-1 increased approximately twofold, similar to rats with experimentally induced placental ischemia. In response, mean arterial pressure increased 17 mmHg, which was completely normalized by HO-1 induction. Unbound circulating VEGF was decreased ∼17% in response to sFlt-1 infusion but was increased ∼50% in response to HO-1 induction. Finally, endothelial function was improved as measured by reductions in vascular expression of preproendothelin mRNA. In conclusion, manipulation of HO-1 presents an intriguing therapeutic approach to the treatment of PE.

Topics: Animals; Antihypertensive Agents; Blood Pressure; Disease Models, Animal; Drug Administration Schedule; Endothelin-1; Endothelium, Vascular; Enzyme Induction; Female; Gestational Age; Heme Oxygenase (Decyclizing); Liver; Placenta; Pre-Eclampsia; Pregnancy; Protoporphyrins; Rats; Rats, Sprague-Dawley; RNA, Messenger; Time Factors; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-1

Although soluble fms-like tyrosine kinase 1 (sFlt-1), an antagonist of vascular endothelial growth factor and placental growth factor, has been implicated in the pathogenesis of hypertension during preeclampsia, the mechanisms whereby enhanced sFlt-1 production leads to hypertension remain unclear. Both sFlt-1 and endothelin 1 productions are elevated in women with preeclampsia and in placental ischemic animal models of preeclampsia; however, the importance of endothelin 1 and sFlt-1 interactions in the control of blood pressure during pregnancy is unknown. The purpose of this study was to determine the role of endothelin 1 in mediating sFlt-1-induced hypertension in pregnant rats. To achieve this goal, sFlt-1 (3.7 microg/kg per day for 6 days) was infused into normal pregnant rats and pregnant rats treated with a selective endothelin type A receptor antagonist, ABT 627 (5 mg/kg per day for 6 days). Plasma concentration of sFlt-1 increased from 735+/-34 pg/mL in normal pregnant rats to 2498+/-645 pg/mL (P<0.05) with infusion of sFlt-1. Arterial pressure increased from 100+/-1 mm Hg in normal pregnant rats to 122+/-3 mm Hg (P<0.05) in sFlt-1-infused rats. Chronic increases in plasma sFlt-1 in normal pregnant rats increased preproendothelin mRNA expression in the renal cortices by approximately 3-fold. In addition, chronic endothelin type A receptor blockade completely abolished the blood pressure response to sFlt-1 in pregnant rats (104+/-3 versus 100+/-1 mm Hg; P<0.05), whereas the endothelin A receptor antagonist had no effect on arterial pressure in NP rats (105+/-2 versus 100+/-1 mm Hg). In conclusion, this study demonstrates that endothelin 1, via endothelin type A receptor activation, plays an important role in mediating the hypertension in response to excess sFlt-1 during pregnancy.

Topics: Analysis of Variance; Animals; Atrasentan; Blood Pressure Determination; Disease Models, Animal; Endothelin Receptor Antagonists; Endothelin-1; Enzyme-Linked Immunosorbent Assay; Female; Hypertension, Pregnancy-Induced; Pre-Eclampsia; Pregnancy; Pregnancy Proteins; Pregnancy, Animal; Probability; Pyrrolidines; Random Allocation; Rats; Rats, Sprague-Dawley; Receptor, Fibroblast Growth Factor, Type 1; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Vascular Endothelial Growth Factor Receptor-1

Hypertensive disorders of pregnancy are characterized by systemic and placental inflammation; however, treatment for these conditions has remained elusive. We tested whether administration of the anti-inflammatory cytokine interleukin-10 (IL-10) during pregnancy would attenuate the hypertension, endothelial dysfunction, proteinuria, and inflammation seen in pregnant DOCA/saline-treated (PDS) rats. Normal pregnant (NP) rats and PDS were given daily intraperitoneal injections of recombinant IL-10 from gestational day 13 until death on day 20. Systolic blood pressure, aortic endothelium-dependent relaxation responses, and urinary protein excretion were measured on days 13 and 20 of gestation. Fetal number and development, plasma endothelin-1 levels, serum and placental levels of IFNgamma and IL-10, and aortic and placental levels of platelet endothelial cell adhesion molecule (PECAM) were assessed on gestational day 20. Systolic blood pressure, aortic endothelial dysfunction, and urinary protein excretion were significantly increased at gestational day 13 in PDS rats. However, all of these were restored to NP levels following IL-10 treatment in PDS rats. IL-10 treatment also significantly increased the number of pups per litter in PDS rats and did not further affect fetal development. The beneficial effects of IL-10 in PDS rats were likely mediated by the decreased plasma levels of endothelin-1, decreased levels of circulating and placental IFNgamma, as well as decreased aortic and placental expression of PECAM. These data demonstrate that exogenous IL-10 can normalize blood pressure and endothelial function in pregnancy-induced hypertensive rats and may be beneficial in women with hypertensive disorders of pregnancy.

Topics: Animals; Aorta; Blood Pressure; Congenital Abnormalities; Disease Models, Animal; Endothelin-1; Endothelium, Vascular; Female; Hypertension, Pregnancy-Induced; Inflammation; Interferon-gamma; Interleukin-10; Litter Size; Male; Placenta; Platelet Endothelial Cell Adhesion Molecule-1; Pre-Eclampsia; Pregnancy; Proteinuria; Rats; Rats, Sprague-Dawley; Recombinant Proteins

The cause of preeclampsia remains unknown. Excessive antiangiogenic proteins have been proposed to play a pathogenic role in preeclampsia.. Our objective was to determine the differences in soluble endoglin (sEndoglin), soluble fms-like tyrosine kinase receptor-1 (sFLT1), leptin, adiponectin, and endothelin 1 concentrations between normal and preeclampsia amniotic fluid (AF). Such results may help us understand the pathophysiology of preeclampsia.. We performed a nested case-control study. Seventy-one women with preeclampsia were matched to 71 normotensive controls. The preeclamptic women were broken into two subgroups according to the association with fetal intrauterine growth restriction (IUGR). AF concentrations of sEndoglin, sFLT1, leptin, adiponectin, and endothelin 1 were measured by ELISA. Receiver-operating characteristics curve analysis was used to compare the discriminative values of these potential biomarkers. Functional network analysis was performed using MetaCore to reveal the common functions of the interacting proteins.. Increased AF concentrations of sFLT1, sEndoglin, endothelin 1, and leptin were found in women who later developed preeclampsia. sFLT1, sEndoglin, leptin, and adiponectin were significantly higher in the preeclampsia with IUGR than those without IUGR. Leptin has the largest area under the curve (0.753). Network analysis revealed that elevated amniotic proteins are involved in the inflammatory process of the human placenta.. Significant elevation of leptin can be detected in AF 2 months earlier than the appearance of symptoms; thus, it may be used as a predictive marker for preeclampsia. The increase of these antiangiogenic proteins supports the roles of inflammation and oxidative stress in pathogenesis of preeclampsia.

Topics: Adiponectin; Adult; Amniotic Fluid; Analysis of Variance; Antigens, CD; Case-Control Studies; Chi-Square Distribution; Endoglin; Endothelin-1; Enzyme-Linked Immunosorbent Assay; Female; Fetal Growth Retardation; Humans; Leptin; Pre-Eclampsia; Predictive Value of Tests; Pregnancy; Prospective Studies; Receptors, Cell Surface; Regression Analysis; ROC Curve; Vascular Endothelial Growth Factor Receptor-1

To investigate the expression levels of serum soluble Endoglin (sEng), plasma endothelin-1 (ET-1) and coagulation function in patients suffering from early onset severe preeclampsia with organ dysfunction, and to analyze the clinical significance.. Forty-nine early onset severe preeclampsia patients were enrolled in the study group, including 26 cases without organ dysfunction (study group I) and 23 cases with organ dysfunction (study group II). The control group included 30 cases of health pregnant women during the same period of gestation. The serum levels of sEng and plasma ET-1 were analyzed with enzyme-linked immunosorbent assay (ELISA), coagulation function was determined at the same time, and the relationship between the change in levels of sEng, ET-1, coagulation function and organ function, and also outcome of perinatal infants.. (1) The levels of sEng, ET-1, fibrinogen (Fib) and mean platelet volume (MPV) of the study group I and II were significantly higher compared with control group (sEng, microg/L: 10.96+/-3.21, 14.17+/-4.02 vs. 7.49+/-2.73; ET-1, microg/L: 41.54+/-10.37, 65.91+/-12.46 vs. 24.56+/-6.26; Fib, g/L: 4.41+/-1.02, 5.35+/-1.17 vs. 3.69+/-0.82; MPV, fl: 11.71+/-1.21, 13.89+/-1.76 vs. 11.03+/-0.82, all P<0.05), and prothrombin time (PT), activated partial thromboplastin time (APTT) and platelet (PLT) were significantly lower compared with control group (PT, s: 10.73+/-1.82, 8.37+/-1.51 vs. 12.95+/-1.91; APTT, s: 26.14+/-4.32, 22.69+/-3.77 vs. 30.25+/-4.71; PLT, x10(9)/L: 164.17+/-50.67, 136.43+/-51.21 vs. 201.63+/-59.83, all P<0.05). There were also statistical significances in all the values between study group I and II (all P<0.05). (2) There was positive correlation between the sEng level and systolic pressure, diastolic pressure, Fib, urine protein of 24 hours, serum creatinine (SCr); there was negative correlation between the sEng level and albumin (Alb) content, PT, estriol/creatinine (E/C) of 12-hour urine, fetal birth weight (all P<0.01). There was positive correlation between the level of ET-1 and the systolic pressure, diastolic pressure, Fib, urine protein of 24 hours, SCr, or alanine aminotransferase (ALT); there was negative correlation between the level of ET-1 and Alb, PT, E/C of 12-hour urine, or fetal birth weight (P<0.05 or P<0.01). (3)In the study group, the occurrence rate of the heart, kidney and lung dysfunction, placental abruption and perinatal death of infants increased (69.23% vs. 11.11%, 38.46% vs. 2.78%, 38.46% vs. 2.78%, 46.15% vs. 2.78%, 53.85% vs. 2.78%, all P<0.01) when the content of sEng>or=16 microg/L compared with sEng<16 microg/L; the occurrence rate of heart, kidney, liver and lung dysfunction, placental abruption and perinatal death of infants increased (64.28% vs. 11.43%, 35.71% vs. 2.86%, 28.57% vs. 5.71%, 28.57% vs. 5.71%, 35.71% vs. 5.71%, 42.86% vs. 5.71%, all P<0.01) when the level of ET-1>or=70 microg/L compared with ET-1<70 microg/L; the occurrence rate of multiple organ dysfunction syndrome was 90% (9/10) when PT<7 s, APTT<20 s and PLT<100x10(9)/L.. The elevation of levels of serum sEng, plasma ET-1 and coagulation abnormality may contribute to the pathogenesis of the organ dysfunction in early onset severe preeclampsia, and the detection of the above-mentioned indexes has important clinical value.

Topics: Antigens, CD; Blood Coagulation; Endoglin; Endothelin-1; Female; Humans; Multiple Organ Failure; Pre-Eclampsia; Pregnancy; Prospective Studies; Receptors, Cell Surface

To explore the role of endothelin-1 (ET-1) and leptin in intrauterine growth restriction (IUGR) among preeclamptic and non-pre-eclamptic women.. Forty three patients with a pregnancy complicated by IUGR, 23 cases with severe pre-eclampsia and 20 cases of non-pre-eclamptic were enrolled. Control group comprised 15 cases with uncomplicated pregnancy. Blood samples from umbilical artery and maternal venous blood were collected at the time of delivery for analysis of ET-1 and leptin levels. Mode of delivery, birth weight and Apgar score were also recorded.. The mean maternal and fetal ET-1 level was significantly higher in pregnancies complicated by IUGR than in control group. The mean maternal leptin level was significantly higher in pre-eclamptic patients when compared to non-preeclamptic and control groups. Mean fetal leptin level was significantly lower in patients compared to control; however, when fetal leptin corrected to fetal weight, it was insignificantly different in the both groups. E-mail: m. alhaggar@yahoo.co.uk.. Maternal plasma ET-1 and leptin correlate with the degree of fetal growth restriction originating from deterioration of placental function. Maternal plasma leptin and ET-1 levels may reflect deterioration in fetal growth.

Topics: Adult; Analysis of Variance; Biomarkers; Birth Weight; Case-Control Studies; Chi-Square Distribution; Endothelin-1; Enzyme-Linked Immunosorbent Assay; Female; Fetal Growth Retardation; Gestational Age; Humans; Infant, Newborn; Leptin; Linear Models; Maternal Age; Pre-Eclampsia; Predictive Value of Tests; Pregnancy; Pregnancy Outcome; Prenatal Care; Probability; Reference Values; Sensitivity and Specificity; Severity of Illness Index; Ultrasonography, Prenatal; Young Adult

Agonistic autoantibodies to the angiotensin II type I receptor (AT1-AA) and endothelin -1 (ET-1) are suggested to be important links between placental ischemia and hypertension during preeclampsia. Activation of the angiotensin II type 1 receptor (AT1R) increases endothelial cell production of ET-1; however, the importance of ET-1 in response to AT1-AA-mediated AT1 R activation during preeclampsia is unknown. Furthermore, the role of AT1-AA-mediated increases in blood pressure during pregnancy remains unclear. The objective of this study was to test the hypothesis that AT1-AA, increased to levels observed in preeclamptic women and placental ischemic rats, increases mean arterial pressure (MAP) by activation of the ET-1 system. Chronic infusion of purified rat AT1-AA into normal pregnant (NP) rats for 7 days increased AT1-AA from 0.68+/-0.5 to 10.88+/-1.1 chronotropic units (P<0.001). The increased AT1-AA increased MAP from 99+/-1 to 119+/-2 mm Hg (P<0.001). The hypertension was associated with significant increases in renal cortices (11-fold) and placental (4-fold) ET-1. To determine whether ET-1 mediates AT1-AA-induced hypertension, pregnant rats infused with AT1-AA and NP rats were treated with an ET(A) receptor antagonist. MAP was 100+/-1 mm Hg in AT1-AA+ET(A) antagonist-treated rats versus 98+/-2 mm Hg in ET(A) antagonist-treated rats. Collectively, these data support the hypothesis that one potential pathway whereby AT1-AAs increase blood pressure during pregnancy is by an ET-1-dependent mechanism.

Topics: Animals; Atrasentan; Autoantibodies; Blood Pressure; Disease Models, Animal; Endothelin A Receptor Antagonists; Endothelin-1; Female; Hypertension; Kidney; Placenta; Pre-Eclampsia; Pregnancy; Pregnancy, Animal; Pyrrolidines; Rats; Rats, Sprague-Dawley; Receptor, Angiotensin, Type 1

Preeclampsia, a pregnancy-specific syndrome characterized by hypertension and proteinuria, has a familial tendency and is an important cause of maternal and neonatal mortality. Abnormal endothelin-1 synthesis and/or release can explain abnormalities seen in preeclampsia. We prospectively evaluated whether endothelin-1 levels are increased in preeclampsia, to verify if placenta is the source, and any association between the maternal EDN1 G5665T single-nucleotide polymorphism and circulating endothelin-1 levels and preeclampsia manifestation.. A total of 120 with preeclampsia and 118 normotensive primigravid patients with singleton pregnancy were enrolled. Preeclampsia was defined as new onset of elevated blood pressure greater than 140/90 mmHg and at least 2+ proteinuria on two occasions at least 4 h apart after 20 weeks of gestation in previously normotensive pregnant women. Patients were excluded if they had hypertension before 20 weeks of gestation, diabetes, asthma, heart disease, kidney disease, hematological disorder, autoimmune disease, urinary tract infection, current or past history of smoking, twin pregnancy, molar pregnancy or eclampsia. Genotyping was done using a PCR-RFLP-based method. Placenta samples were collected from 20 preeclampsia and 24 normotensive pregnancies. Reverse transcriptase PCR was done for preproendothelin and beta-actin mRNA. Placental endothelin-1 staining was assessed by immunohistochemistry in villous and extravillous trophoblasts and endothelium. Plasma endothelin-1 levels were measured using ELISA.. The preeclampsia group showed higher circulating endothelin-1 levels (1.45 +/- 0.55 vs. 0.91 +/- 0.42 pg/ml; P < 0.0001), reduced frequency of GG genotype (34 vs. 49%; P = 0.025) and increased T allele frequency (0.43 vs. 0.28; P = 0.04). A significant association was noted between endothelin-1 levels and blood pressure in the entire cohort and in the group with preeclampsia (P < 0.001). Circulating endothelin-1 levels were higher in those bearing even one copy of the T variant (1.08 +/- 0.48 vs. 1.31 +/- 0.59 pg/ml; P = 0.004). Placental endothelin-1/beta-actin mRNA ratio was significantly reduced (0.91 +/- 0.77 vs. 3.20 +/- 1.68; P < 0.001) and endothelin-1 staining was lower (P < 0.001) in placental endothelium in preeclampsia.. Maternal endothelin-1 is elevated and correlates with the severity of blood pressure elevation in preeclampsia. The endothelin-1 is likely released from the maternal endothelium. Presence of T allele at 5665 position in maternal EDN1 gene is associated with higher endothelin-1 levels. Placental endothelin-1 synthesis is reduced in preeclampsia. The combination of elevated maternal and reduced placental endothelin-1 may be an adaptive response to reduced uteroplacental flow in preeclampsia.

Topics: Adult; Endothelin-1; Female; Gene Frequency; Genotype; Humans; Immunohistochemistry; Phenotype; Placenta; Polymorphism, Restriction Fragment Length; Polymorphism, Single Nucleotide; Pre-Eclampsia; Pregnancy; RNA, Messenger; Young Adult

Preeclampsia (PE) is a multisystem disorder that remains a major cause of maternal and foetal morbidity and death. To date, no treatment has been found that prevents the development of the disease. Endothelial dysfunction is considered to underlie its clinical manifestations, such as maternal hypertension, proteinuria and edema; and oxidative stress has been increasingly postulated as a major contributor to endothelial dysfunction in PE. A large body of research has investigated the potential role of antioxidant nutrients in the prevention of PE in women at high increased risk of the disease. Therefore, the present study was primary designed to assess the potential benefit of antioxidant supplementation on markers of placental oxidative stress in an in vitro model of PE, since we previously found that endothelin-1 (ET-1) is able to trigger the placental secretion of stress molecules. In this regard, we evaluated the effects of vitamin C, vitamin E and N-acetylcysteine (NAC), alone or in combination, in placental villi culture after exposure to ET-1. The effect of antioxidant nutrients on trophoblast cells proliferation and vitality was also evaluated. The results obtained suggest that in a pathophysiological condition, such as PE, the deleterious effect of reactive oxygen species may be counteract by an antioxidant therapy, and there is the need to investigate the optimum dosing and timing of antioxidants administration, since an inappropriate antioxidant treatment in pregnant women may have deleterious consequences, reducing placental cells proliferation until to cell death.

Topics: Acetylcysteine; Adult; Antioxidants; Ascorbic Acid; Cell Line, Tumor; Cell Proliferation; Cell Survival; Endothelin-1; Female; Glutathione; Humans; Lipid Peroxidation; Malondialdehyde; Oxidative Stress; Placenta; Pre-Eclampsia; Pregnancy; Vitamin E; Young Adult

The aim of this study was to determine several parameters of nitric oxide metabolism in pre-eclamptic patients.. We conducted a nested case-control study at the Department of Obstetrics and Gynecology, São José Hospital, Brazil. Thirty-five pre-eclamptic and 35 normotensive pregnant women were included in the study. Pre-eclampsia was diagnosed as an increase in diastolic blood pressure (BP) of 15 mm Hg and systolic BP of 30 mm Hg at two measurements at least 4 h apart, compared with BP obtained before 20 weeks of gestation, and proteinuria > 0.3 g/24 h in the absence of urinary tract infection. Fasting peripheral venous blood samples were obtained during the antepartum period in pre-eclamptic and control (matched for maternal age and gestational age) patients.. Plasma nitrite was significantly lower and plasma endothelin levels were significantly higher in pre-eclamptic women than in normotensive pregnant women. Superoxide dismutase activity was decreased and arginase activity was significantly increased in pre-eclamptic patients when compared to normotensive pregnant women.. We suggested that in pre-eclampsia excessive arginase and low superoxide dismutase activity leads to a decrease nitric oxide levels and oxidative stress, and this may promote microvascular oxidative damage and endothelial dysfunction.

Topics: Adult; Arginase; Case-Control Studies; Endothelin-1; Female; Humans; Nitric Oxide; Pre-Eclampsia; Pregnancy; Superoxide Dismutase; Young Adult

To investigate the relationship between neurokinin B (NKB), endothelin-1 (ET-1) and the pathogenesis of hypertensive disorder complicating pregnancy (HDCP).. 22 HDCP, who received antenatal examination in the Department of Obstetrics and Gynecology of Union Hospital of Tongji Medical College in Huazhong University of Science and Technology from March to July in 2005, were selected for the study, including 12 gestational hypertension (gestational hypertension group) and 10 preeclampsia (preeclamptic group); 22 normal pregnant women in the same period were served as control. At different gestational weeks, maternal plasma levels of NKB and ET-1 in three groups were detected by enzyme-linked immunoassay technique, the expression and location of NKB in placenta were examined by immunohistochemical SP, and mRNA expressions of NKB and ET-1 in placenta were measured with RT-PCR method.. (1) At 10 - 14, 20 - 24, and 30 - 34 gestational weeks, the plasma levels of NKB and ET-1 in preeclamptic group were (35.6 +/- 5.2), (17.9 +/- 4.3), (39.5 +/- 4.3), (22.7 +/- 3.6), (47.1 +/- 3.3) and (27.5 +/- 3.5) microg/L, respectively; in the control group they were (22.9 +/- 3.3), (10.7 +/- 5.3), (30.2 +/- 3.4), (13.2 +/- 4.1), (34.6 +/- 4.3) and (16.6 +/- 4.8) microg/L, respectively. There was a significant difference between preeclamptic group and control group (P < 0.05), while there was no significant difference between gestational hypertension group and control group (P > 0.05). (2) Immunohistochemical staining for NKB protein was observed in all groups and was located in the villous syncytiotrophoblast and villous vascular endothelial cells as well as cytoplasm of stromal cells, mostly located in villous syncytiotrophoblast. The expressions of NKB in placenta of preeclamptic group (0.244 +/- 0.020) was significantly higher than that in control group (0.160 +/- 0.012), with a significant difference between the two groups (P < 0.05). However, there was no significant difference between gestational hypertension group (0.162 +/- 0.019) and control group (P > 0.05). (3) The transcription levels of the NKB mRNA (0.97 +/- 0.36) and ET-1 mRNA (0.90 +/- 0.36) in preeclamptic placentas were both significantly higher than those in control groups (0.78 +/- 0.54, 0.65 +/- 0.47, respectively), with a significant difference between the two groups (P < 0.05). But there was no significant difference between gestational hypertension group (0.80 +/- 0.40, 0.70 +/- 0.32, respectively) and control group (P > 0.05). (4) There was an evident positive correlation between plasma NKB and ET-1 levels in preeclampsia (r = 0.79, P < 0.05).. The significantly increased maternal plasma levels of NKB and ET-1 of patients with preeclampsia occur at early pregnancy (10 - 14 gestational weeks) before the onset of clinical symptoms. The change of maternal plasma levels of NKB and ET-1 is closely related to pathogenesis of HDCP.

Topics: Adult; Case-Control Studies; Endothelin-1; Female; Humans; Hypertension, Pregnancy-Induced; Immunohistochemistry; Neurokinin B; Placenta; Pre-Eclampsia; Pregnancy; Pregnancy Trimesters; Prospective Studies; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Trophoblasts

In preeclampsia (PE), proteinuria has been associated with a reduced expression of nephrin by podocytes. In the present study, we investigated in vitro on human cultured podocytes the mechanism responsible for nephrin loss in PE. Sera from patients with PE did not directly downregulate the expression of nephrin. In contrast, conditioned medium obtained from glomerular endothelial cells incubated with PE sera induced loss of nephrin and synaptopodin, but not of podocin, from podocytes. Nephrin loss was related to a rapid shedding of the protein from the cell surface due to cleavage of its extracellular domain by proteases and to cytoskeleton redistribution. The absence of nephrin mRNA downregulation together with nephrin reexpression within 24 h confirm that the loss of nephrin was not related to a reduced synthesis. Studies with an endothelin-1 (ET-1) receptor antagonist that abrogated the loss of nephrin triggered by glomerular endothelial conditioned medium of PE sera indicated that ET-1 was the main effector of nephrin loss. Indeed, ET-1 was synthesized and released from glomerular endothelial cells when incubated with PE sera, and recombinant ET-1 triggered nephrin shedding from podocytes. Moreover, VEGF blockade induced ET-1 release from endothelial cells, and in turn the conditioned medium obtained triggered nephrin loss. In conclusion, the present study identifies a potential mechanism of nephrin loss in PE that may link endothelial injury with enhanced glomerular permeability.

Topics: Animals; Blotting, Western; Cell Line; Endothelial Cells; Endothelin-1; Enzyme-Linked Immunosorbent Assay; Extracellular Matrix; Female; Flow Cytometry; Fluorescent Antibody Technique; Guinea Pigs; Humans; Immunoprecipitation; Intracellular Signaling Peptides and Proteins; Kidney Glomerulus; Membrane Proteins; Podocytes; Pre-Eclampsia; Pregnancy; Reverse Transcriptase Polymerase Chain Reaction; Serum

To investigate the mechanism of vascular endothelial growth factor (VEGF)-induced endothelin-1 production in human umbilical vein endothelial cells (HUVECs).. Endothelin-1 levels were measured in conditioned medium of women with preeclampsia HUVECs were treated with different concentrations of VEGF(165) and at various time intervals. Next, we measured endothelin-1 levels after HUVECs were also incubated with VEGF and endothelin-converting enzyme-1 (ECE-1) inhibitor or tissue inhibitors of matrix metalloproteinase-2 (TIMP-2). Additionally, the circulating levels of total and free VEGF, matrix metalloproteinase-2 (MMP-2), and endothelin-1 were measured in 20 preeclamptic patients and 20 healthy pregnant controls.. HUVECs treated with VEGF increased their endothelin-1 production in a concentration and time-dependent manner. The production of endothelin-1 was inhibited by TIMP-2, but not by the ECE-1 inhibitor. Total VEGF, MMP-2, and endothelin-1 concentrations were higher in preeclampsia and showed significant positive correlations between them.. These findings suggest that VEGF-induced endothelin-1 production might be mediated by MMP-2 rather than by ECE-1 upregulation.

Topics: Adult; Analysis of Variance; Aspartic Acid Endopeptidases; Biomarkers; Case-Control Studies; Dose-Response Relationship, Drug; Endothelial Cells; Endothelin-1; Endothelin-Converting Enzymes; Enzyme Inhibitors; Enzyme-Linked Immunosorbent Assay; Female; Humans; Korea; Matrix Metalloproteinase 2; Matrix Metalloproteinase Inhibitors; Metalloendopeptidases; Pre-Eclampsia; Pregnancy; Time Factors; Treatment Outcome; Umbilical Veins; Vascular Endothelial Growth Factor A

To investigate the effects of magnesium sulphate (MgSO(4)) on placental expression of endothelin 1 (ET-1) and its receptors in preeclampsia (PE).. Placentas were obtained from 10 normotensive (NT group) and 18 moderate preeclamptic (PE group) women. Among the PE group, 10 patients were treated with 0.9% NaCl solution (PES) and 8 women received MgSO(4) (PEMgSO(4)). Placental mRNAs of ET-1, ET-1(A) receptor (ET-1(A)R) and ET-1(B) receptor (ET-1(B)R) were evaluated by Northern blot and quantified using densitometry.. Placental ET-1(B)R expression was lower (P<0.05) in the PES group without significant changes in the mRNAs of ET-1 and ET-1(A)R when compared with the NT group. MgSO(4) treatment was associated with decreased ET-1 and increased ET-1(B)R (P<0.05) expression, without significant changes in ET-1(A)R.. The results of the present study showed that moderate PE is associated with low placental expression of ET-1(B)R, and MgSO(4) treatment resulted in placental expression changes of the ET-1/receptors system.

Topics: Adult; Blotting, Northern; Endothelin-1; Female; Gene Expression Regulation; Humans; Magnesium Sulfate; Placenta; Pre-Eclampsia; Pregnancy; Receptor, Endothelin A; Receptor, Endothelin B; RNA, Messenger

The changes in blood vessel endothelium have impact on pathogenesis of preeclampsia. The aim of the study was establishment of nitric oxide level (NO) and endothelin-1 content in blood during preeclampsia. The level of NO and content of endothelin-1 were studied in blood of healthy reproductive age nonpregnant, practically healthy pregnant patients, and patients with complicated pregnancy (preeclampsia) (III trem). The free NO content was established by electron paramagnetic resonance (EPR) method using spin-trap Na diethil-ditiocarbomate (DETC) (Sigma). Endotheline-1 content was determined by immuno-ensyzatic method with Reagent Kit (Endothelin-1, Cayman Chemical). Free NO level and endothelin-1 content in blood was similar in both--healthy reproductive age nonpregnant women and practically healthy pregnant patients. It was unchanged during physiological pregnancy. During preeclampsia the free NO content was 10% decreased, and endotheline-1 content 71% increased compared to control (physiological pregnancy) level.. during preeclampsia the low activity of endothelial NO-syntheses and redox-dependent transformation of NO in peroxynitrite provoke decrease nitric oxide level in blood. Increase of Endothelin-1 content in blood may be compensatory to low placental perfusion during preeclampsia. High endothelin-1 is cytotoxity, causes intensification of oxidative stress in trophoblasts and disorders of cell membranes of blood vessel endothelium. Free nitric oxide reduction and rising of endothelin-1 level in blood during preeclampsia causes redoubling of endothelial function.

Topics: Endothelin-1; Female; Humans; Hypertension; Nitric Oxide; Pre-Eclampsia; Pregnancy; Pregnancy Complications; Proteinuria

Preeclampsia (PE) is a disorder that occurs only during pregnancy. The placenta has a controlling role in this condition. Recent literature suggests that the oxidative stress is a component of PE and plays a main role in the link between decreased placental perfusion and the impaired function of maternal endothelium.. Because the human placenta expresses endothelin-1 (ET-1) and its circulating levels are high in pregnancies complicated with PE, the present study investigated the role of ET-1 on placental oxidative stress pathways.. Human placental explants, JEG-3, and primary cytotrophoblast cells were cultured with increasing ET-1 concentrations for 6 and 24 h.. The study was conducted at tertiary clinical care centers in Siena and Padova, Italy.. Human placental explants, JEG-3, and primary cytotrophoblast cells were used to test ET-1 effect.. The main outcome measure was ET-1 mRNA and its receptor mRNAs, type A and B, detection by RT-PCR. The common markers of oxidative stress [malondialdehyde (MDA), glutathione (GSH), glutathione disulfide (GSSG), ascorbic acid (AA)] as well as cell proliferation and vitality were measured after stimulation periods.. ET-1 inhibits cell proliferation and vitality and triggers oxidative stress in the human placenta by altering the balance between oxidant (increased MDA levels) and antioxidant (decreased GSH, GSSG, and AA) forces in favor of oxidation.. Because MDA damages endothelial cells, whereas GSH, GSSG, and AA protect them, we postulate that ET-1 may be one of the key links between primary placental disorders and the systemic endothelial dysfunction of PE.

Topics: Cell Line, Tumor; Endothelin-1; Female; Glutathione; Humans; Lipid Peroxidation; Oxidative Stress; Placenta; Pre-Eclampsia; Pregnancy

Impaired placentation and oxidative stress are proposed to play major roles in the pathogenesis of placental dysfunction and pre-eclampsia. This study was carried out to evaluate if inhibited angiogenesis by Suramin injections in early pregnancy may cause a condition resembling pre-eclampsia in rats. Rats of two different Sprague-Dawley strains, U and H, were given intraperitoneal injections of Suramin or saline in early pregnancy. The outcome of pregnancy was evaluated on gestational day 20. Suramin injections caused increased blood pressure and decreased renal blood flow in the U rats. In both rat strains Suramin decreased the placental blood flow and caused fetal growth retardation. In both strains the placental concentration of the isoprostane 8-epi-PGF2alpha was increased, indicating oxidative stress. The serum concentration of Endothelin-1 was increased in the U rats. The U strain had a lower basal placental blood flow, and the effects of Suramin were more pronounced in this strain. We conclude, that Suramin injections to pregnant rats cause a state of placental insufficiency, which partly resembles human pre-eclampsia. The induction of this condition is at least partly mediated by oxidative stress, and is subject to varied genetic susceptibility.

Topics: Angiogenesis Inhibitors; Animals; Blood Pressure; Disease Models, Animal; Electrolytes; Endothelin-1; Female; Humans; Isoprostanes; Lipids; Nitrites; Placenta; Pre-Eclampsia; Pregnancy; Pregnancy Outcome; Proteinuria; Rats; Rats, Sprague-Dawley; Regional Blood Flow; Renal Circulation; Suramin; Weight Gain

The present study was designed to examine the effects of ET-1 (endothelin-1) and serum from PE (pre-eclamptic), HP (healthy pregnant) and HNP (healthy non-pregnant) women on uterine arterial perfusion pressure and uterine contractility. Swine uteri (n = 25) were perfused for a period of up to 11 h, with the aim being to preserve a viable organ. Various concentrations of ET-1 as well as serum from PE, HP and HNP women (n = 10 per group) were administered to the perfused swine uteri and IUP (intrauterine pressure) and IAP (intra-arterial pressure) were recorded. ET-1 produced dose-dependent increases in IUP and IAP. The ET-1 concentration in serum was higher in serum from PE women than in HP and HNP women (P > 0.05). Administration of all serum samples had a contractile effect on the swine uterus, with the greatest effect being seen in HNP women (12.8 +/- 5.3 mmHg), followed by PE (9.06 +/- 4.2 mmHg) and HP (6.1 +/- 4.1 mmHg) women. Statistically significant differences were observed between HNP and PE women (P = 0.048), and PE and HP women (P = 0.021). Increases in IAP following administration of serum from PE women (48.8 +/- 20.0 mmHg) were significantly higher (P = 0.024) compared with the effect of serum from HP women (28.4 +/- 13.7 mmHg). In conclusion, the findings show that serum from PE women has significant vasoconstrictive and oxytocic effects compared with serum from HP women. In pre-eclampsia, the balance between vasorelaxing and vasoactive substances is disturbed.

Topics: Animals; Arteries; Blood Pressure; Endothelin-1; Female; Humans; Organ Culture Techniques; Perfusion; Pre-Eclampsia; Pregnancy; Swine; Uterine Contraction; Uterus; Vasomotor System

To compare serum levels of nitric oxide (NO) and endothelin-1 (ET-1), and urinary concentrations of NO and cyclic guanosine monophosphate (cGMP) between preeclamptic and normotensive pregnant women.. Ninety-one preeclamptic (48 mild, 43 severe) and forty healthy normotensive pregnant women above 32 gestational weeks were recruited into study. Chemiluminesence technique was used for measuring plasma and urinary NO levels, and radioimmunoassay was used to determine plasma ET-1 and urinary cGMP levels.. Plasma and urinary NO, and urinary cGMP levels were significantly lower in preeclamptics than in the control group (respectively, p< 0.001, p< 0.001, p< 0.01). Plasma ET-1 levels were significantly higher in the preeclamptics than in the control group (p<0.001). There were significant negative correlations between plasma ET-1, plasma NO and urinary NO and cGMP in all groups. There were positive correlations between plasma NO, urinary NO and cGMP in all groups.. The imbalance between NO and ET-1 may play a significant role in the pathophysiology of preeclampsia.

Topics: Adult; Case-Control Studies; Cyclic GMP; Endothelin-1; Female; Gestational Age; Humans; Luminescent Measurements; Nitric Oxide; Pre-Eclampsia; Pregnancy; Radioimmunoassay; Regression Analysis; Severity of Illness Index

The aim of this study was to determine the physiologic role for endogenous endothelin in the regulation of vascular tone during normal pregnancy and preeclampsia. The vascular sensitivity to endothelin-1 during pregnancy was studied also.. Forearm blood flow was measured by venous occlusion plethysmography during intra-arterial infusion of phosphoramidon, an endothelin-converting enzyme inhibitor, for 60 minutes, which was followed by co-infusion with endothelin-1 for 30 minutes. Three groups were studied: healthy nonpregnant women, normal pregnant women, and women with preeclampsia.. There was a significant increase in forearm blood flow in the nonpregnant group after phosphoramidon infusion alone (73%+/-37%; P<.05). Phosphoramidon did not change forearm blood flow in pregnant subjects. Co-infusion with endothelin-1 significantly decreased forearm blood flow in both the nonpregnant and normal pregnant women (53%+/-7% and 40%+/-11%, respectively; P<.01). No response to endothelin-1 was found among women with preeclampsia.. The vascular sensitivity to endothelin-1 is not altered during normal pregnancy in contrast to preeclamptic pregnancy, where no effect of endothelin-1 was seen. Reduced endothelin dependence during pregnancy might be one mechanism behind the fall in peripheral vascular resistance.

Topics: Adult; Aspartic Acid Endopeptidases; Case-Control Studies; Endothelin-1; Endothelin-Converting Enzymes; Female; Forearm; Glycopeptides; Humans; Metalloendopeptidases; Pre-Eclampsia; Pregnancy; Protease Inhibitors; Regional Blood Flow; Vasomotor System

The mechanism of pre-eclampsia is still an enigma. There is now some evidence that amniotic concentrations of endothelin is elevated in pregnancies associated with pre-eclampsia. The aim of this prospective observational study was to record the concentration of amniotic fluid endothelin and compare this in women who develop pre-eclampsia and women who do not develop pre-eclampsia. Amniotic fluid concentration of endothelin is elevated by the second trimester in women who later develop pre-eclampsia.

Topics: Adult; Amniotic Fluid; Birth Weight; Endothelin-1; Female; Humans; Pre-Eclampsia; Pregnancy; Pregnancy Trimester, Second

At present it is unclear whether endothelial activation is systematically present in preeclampsia or restricted to specialized vascular beds. Therefore, this study aimed to investigate the presence of generalized proinflammatory endothelial activation in severe, early-onset preeclampsia in vivo.. During caesarean section, biopsies were obtained from abdominal subcutaneous fat, abdominal fascia, and myometrium from 11 severe, early-onset preeclamptic and 19 healthy pregnant women. Prior to caesarean, section plasma levels of von Willebrand Factor (vWF), sVCAM-1, and C-reactive protein (CRP) were measured by ELISA. Consecutive cryostat sections were stained immunohistochemically for CD31, E-selectin, VCAM-1, and ICAM-1. For subcutaneous fat tissue, endothelial gene expression levels of E-selectin, VCAM-1, ICAM-1, endothelin-1 (ET-1), and endothelial nitric oxide synthase (eNOS) were quantified by real-time RT-PCR, using normalization to the endothelium-specific housekeeping genes CD31 and VE-cadherin.. Plasma levels of vWF, sVCAM-1, and CRP were elevated in the preeclampsia group compared to the control group, indicating enhanced endothelial activation and inflammatory response in the severely diseased preeclamptic women. By immunohistochemical analysis, no E-selectin and VCAM-1 expression could be detected in, and no differences in endothelial ICAM-1 staining could be observed between the preeclampsia and the control group for all tissues studied. Endothelial gene expression levels of E-selectin, VCAM-1, ICAM-1, ET-1, and eNOS were comparable between the preeclampsia and control group.. Protein and gene expression analysis of E-selectin, VCAM-1, ICAM-1, ET-1, and eNOS, key mediators involved in pro-inflammatory endothelial activation, could not identify endothelial activation in severe, early-onset preeclampsia in the tissues studied. However, elevated plasma levels of markers of endothelial activation and inflammation were observed. These results may suggest that in severe, early-onset preeclampsia pro-inflammatory endothelial cell activation is not a generalized phenomenon, but is likely restricted to (possibly organ-specific) specialized vascular beds.

Topics: Adult; Biopsy; E-Selectin; Endothelin-1; Endothelium, Vascular; Female; Gene Expression Profiling; Humans; Immunohistochemistry; Inflammation; Intercellular Adhesion Molecule-1; Pre-Eclampsia; Pregnancy; Reverse Transcriptase Polymerase Chain Reaction; Severity of Illness Index; Vascular Cell Adhesion Molecule-1

To evaluate the relationship of endothelin 1 (ET-1) and leptin concentrations in women and newborns following a pregnancy complicated with intrauterine growth restriction (IUGR).. Twenty-five women with a pregnancy complicated with IUGR at 19 different gestational ages were matched with women with uncomplicated pregnancies. Blood samples from the umbilical artery and maternal peripheral venous circulation were collected at delivery, and ET-1 and leptin levels were determined from the blood samples. Data relating to obstetric complications (e.g., pregnancy-induced hypertension), delivery (e.g. mode, birth weight, signs of intrapartum fetal distress, and Apgar scores) were also recorded.. Mean maternal ET-1 (13.4+/-6.2-9.9+/-2.9 pmol/l) and mean fetal ET-1 (14.5+/-4.2-11.7+/-3.1 pmol/l) concentrations were significantly higher when women had experienced pregnancies complicated with IUGR than when they had had normal pregnancies. Mean fetal leptin concentration was significantly lower in the study group (6.8+/-2.2 ng/ml) than in the control group (10.6+/-3.6 ng/ml (P<0.05). However, fetal leptin per kilogram of fetal weight was not significantly different in the study group (3.16+/-1.18 ng/ml) than in the control group (3.23+/-0.96 ng/ml) (P>0.05, paired t-test). However, a statistically significant correlation was observed between fetal leptin concentrations per kilogram of fetal weight and fetal endothelin concentrations in pregnancies complicated with IUGR (r=0.546; P<0.05).. These results suggest the intertwined roles of ET-1 and leptin in the pathophysiology of IUGR. Further studies concerning interaction between these peptides in different pregnancy conditions may provide important information about the actions of ET-1 and leptin on fetal growth.

Topics: Adult; Birth Weight; Body Mass Index; Case-Control Studies; Endothelin-1; Female; Fetal Blood; Fetal Growth Retardation; Gestational Age; Humans; Infant, Newborn; Leptin; Pre-Eclampsia; Pregnancy; Regression Analysis

The purpose of this study was to determine plasma malondialdehyde (MDA), superoxide dismutase (SOD), soluble E-selectin (sE-selectin), fibronectin, endothelin-1 (ET-1) and nitric oxide (NO) levels in women with preeclampsia and to find out the relations of diastolic blood pressure with these variables.. We performed a case-control study consisting of randomly selected 34 healthy pregnant women and 35 patients diagnosed as preeclampsia. Lipoperoxidation was ascertained by the formation of MDA. SOD activity was determined by the method of Sun et al. Plasma concentration of NO was estimated using colorimetric assay. Plasma ET-1 and sE-selectin were measured by enzyme-linked immunosorbent assay (ELISA). A nephelometric method for fibronectin quantitation was used.. The mean plasma level of MDA was significantly higher and SOD was significantly lower in preeclamptic pregnancies (P<0.001). Plasma concentrations of fibronectin, sE-selectin and ET-1 were significantly increased, whereas NO was significantly decreased in women with preeclampsia than normotensive women (P<0.001).. Increased plasma levels of MDA, fibronectin, sE-selectin, ET-1, and decreased plasma levels of NO and SOD in preeclamptic patients suggest that poorly perfused fetoplacental unit is the origin of oxygen free radicals and lipid peroxides.

Topics: Adult; Biomarkers; Blood Pressure; Case-Control Studies; E-Selectin; Endothelin-1; Female; Fibronectins; Free Radicals; Humans; Malondialdehyde; Nitric Oxide; Pre-Eclampsia; Pregnancy; Superoxide Dismutase

The aim of our study was to compare the expression of leukocyte adhesion molecules, intracellular reactive oxygen species, and vasoactive substances in preeclampsia and matched normotensive pregnancies and to explore differences between pregnancy and the nonpregnant state regarding these parameters.. Flow cytometry was used to analyze the monocyte and granulocyte expression of adhesion molecules from 20 matched pairs of preeclampsia/normotensive pregnancies and 12 nonpregnant subjects. Basal levels of CD11b, CD11c, CD62L, and CD14 were measured. In addition, expression of human lymphocyte antigen-DR, CD4, CD8, and CD4/CD8 ratio were assessed. Basal reactive oxygen species levels, as well as reactivity upon in vitro stimulation with phorbol 12-myristate 13-acetate, were measured in monocytes and granulocytes with the probes dihydroethidium, dichlorofluorescein-diacetate, and dihydrorhodamine-123. Further, the plasma levels of endothelin-1, the nitric oxide metabolites nitrite/nitrate, and total antioxidant status were analyzed.. Monocytes expressed significantly higher levels of CD11b and CD14 in preeclamptic patients compared with normotensive pregnant subjects, whereas CD11c was elevated on both monocytes and granulocytes in pregnancy compared with the nonpregnant state. Both monocytes and granulocytes displayed higher basal, as well as phorbol 12-myristate 13-acetate-stimulated, amounts of reactive oxygen species in the preeclampsia group compared with the normotensive group. We also found the endothelin-1 and antioxidant levels significantly elevated in preeclampsia patients compared with normotensive subjects, whereas no differences were seen between the groups regarding nitrite/nitrate levels.. These results show that the maternal blood leukocytes are activated in preeclampsia and support the view that oxidative stress is a contributing factor in the pathophysiology of preeclampsia.

Topics: Adult; Antioxidants; Cell Adhesion Molecules; Endothelin-1; Female; Granulocytes; Humans; Monocytes; Nitric Oxide; Pre-Eclampsia; Pregnancy; Reactive Oxygen Species

The aim of this study was to determine the normality or otherwise of neurohormone indices, particularly the sympathetic nervous system, in pre-eclamptic patients and document whether changes in body posture magnify any differences between pre-eclamptic and normal women. We studied 11 women with pre-eclampsia and compared them with 17 matched normotensive pregnant women and eight nonpregnant women. Measurements of arterial pressure, heart rate and neurohormones were carried out with subjects in the left lateral position, then supine, left lateral, with upright posture and finally with assumption of the left lateral position again. Main outcome measures were arterial pressure, heart rate and hormones (plasma norepinephrine, renin activity, natriuretic peptides and endothelin-1). We observed that plasma norepinephrine levels were higher in pre-eclamptic than normotensive pregnant women and this was most obvious in the upright position. Plasma renin activity was likewise higher in pre-eclamptic than normotensive pregnant women, again most obvious with upright posture. Plasma natriuretic peptides and endothelin-1 levels were similar in pre-eclamptics and normotensive pregnant women. These data strengthen the premise that pre-eclampsia is associated with sympathetic overactivity as reflected by plasma norepinephrine levels, most obviously observed in the upright position.

Topics: Adult; Analysis of Variance; Blood Pressure; Endothelin-1; Female; Heart Rate; Humans; Natriuretic Peptides; Norepinephrine; Posture; Pre-Eclampsia; Pregnancy; Pregnancy Complications, Cardiovascular; Renin; Sympathetic Nervous System

To determine whether alterations in second-trimester maternal serum cytokine concentrations can identify women at risk for developing severe, early-onset preeclampsia.. Patients with severe preeclampsia requiring delivery prior to 34 weeks (n = 20) were each matched by gestational age, gravidity, parity, and sample freezing time with three healthy controls who delivered at term (n = 60). By using second-trimester maternal sera originally collected for fetal aneuploidy screening, the concentrations of placental growth factor, vascular endothelial growth factor, granulocyte colony-stimulating factor, endothelin-1, and human chorionic gonadotropin were compared between patients and controls. Logistic regression analysis was used to estimate odds ratios for high versus low (median split) cytokine concentrations with respect to the development of severe, early-onset preeclampsia. Receiver operating characteristic (ROC) curves based on a second logistic regression, using actual cytokine values, were plotted to illustrate reciprocal impact on sensitivity and specificity.. Placental growth factor and vascular endothelial growth factor levels were significantly lower in patients than in controls. No significant differences were observed for the other cytokines. The odds ratios (with 95% confidence intervals) were 15.54 (3.29, 73.40) for vascular endothelial growth factor and 4.20 (1.35, 13.06) for placental growth factor. Receiver operating characteristic analysis of placental growth factor and vascular endothelial growth factor confirmed that both were useful in discriminating between patients and controls. Models combining both vascular endothelial growth factor and placental growth factor provided the best performance for identifying patients at risk for developing severe, early-onset preeclampsia, according to both odds ratios and ROC analyses.. Combined analysis of placental growth factor and vascular endothelial growth factor is potentially useful as a tool for early identification of patients at risk for developing severe, early-onset preeclampsia.

Topics: Case-Control Studies; Chorionic Gonadotropin; Endothelial Growth Factors; Endothelin-1; Female; Granulocyte Colony-Stimulating Factor; Humans; Intercellular Signaling Peptides and Proteins; Logistic Models; Lymphokines; Placenta Growth Factor; Pre-Eclampsia; Pregnancy; Pregnancy Proteins; Pregnancy Trimester, Second; Risk; ROC Curve; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors

The aim of this study was to determine the effect of treatment on endotelin-1 concentration that is considered to have role in etiopathogenesis of eclampsia and preeclampsia.. Nine patients with eclampsia and 12 patients with preeclampsia were included to the study. Endothelin-1 levels were measured before and after magnesium sulfate treatment. After the magnesium sulfate administration, if the blood pressure was still elevated, nifedipine was given.. Endothelin-1 levels of preeclamptic patients before and after magnesium sulfate treatment were 16.9 +/- 2.3 fmol/ml and 14.6 +/- 1.9 fmol/ml respectively (p < 0.05). The same measurements of eclamptic patients were 18.1 +/- 3.2 and 14.7 +/- 3.4 respectively (p < 0.05). The mean blood pressures of preeclamptic patients before and after magnesium sulfate were 125.8 +/- 7.3 mm-Hg, 118.2 +/- 8.7 mm-Hg respectively, and the same measurements of eclamptic patients were 136.0 +/- 12.4 mm-Hg and 123.1 +/- 10.6 mm-Hg respectively (p < 0.05, p < 0.05).. Treatment had been found to have negative effects on endothelin-1 levels that is considered to play an important role on etiopathogenesis of eclampsia and preeclampsia.

Topics: Adult; Biomarkers; Blood Pressure; Blood Pressure Determination; Eclampsia; Endothelin-1; Female; Humans; Magnesium Sulfate; Pre-Eclampsia; Pregnancy; Pregnancy Outcome; Pregnancy Trimester, Third; Probability; Prospective Studies; Risk Assessment; Statistics, Nonparametric; Treatment Outcome

Enhanced production of endothelin-1, due to endothelial cell dysfunction has been considered to be the cause of increased plasma levels of endothelin-1 in preeclampsia. The present study was aimed at analyzing endothelin-converting-enzyme activity, (which reflect the production rate of endothelin-1 (ET-1) from big endothelin-1 (big ET-1)), big endothelin-1, and endothelin-1 concentrations from women with preeclampsia compared to normal pregnant women. Moreover, we analyzed plasma levels of these substances longitudinally throughout normal pregnancy.. Twenty-nine pregnant healthy women were recruited to the study. Blood samples were obtained at 18, 28, and 38 weeks gestation and six weeks postpartum. Twenty-seven women with preeclampsia were included. Blood samples were taken at diagnosis (average 35 weeks gestation; range 27-39 weeks) and six weeks postpartum. Endothelin-1 was analyzed by enzyme linked immunoassay (ELISA) and big-ET-1 by radioimmunoassay (RIA). Endothelin-converting-enzyme activity was measured using big endothelin-1 as a substrate and thiorphan as an inhibitor of serum neutral endopeptidase. The amount of endothelin-1 generated during one hour was measured by RIA. Mean +/- SEM is given.. In normal pregnancy endothelin-1 concentrations at 38 weeks and postpartum were increased by 30% (p < 0.01) and 50% (p < 0.001), respectively compared with the second trimester values. Endothelin-converting-enzyme activity did not change. At diagnosis endothelin-1 was higher in women with preeclampsia than in the controls at 38 weeks (0.96 +/- 0.07 vs. 0.64 +/- 0.06 pmol/L; p < 0.001). Likewise, endothelin-converting-enzyme activity was higher in the preeclampsia group (222 +/- 15 vs. 172 +/- 8 pmol ET/ml/h; p < 0.01). This difference remained at six weeks postpartum.. Our findings imply enhanced ET-1 production in preeclampsia. The elevated endothelin-converting-enzyme activity postpartum may indicate an inherent endothelial dysfunction predisposing to preeclampsia or that preeclampsia may cause irreversible changes in endothelial function.

Topics: Adult; Aspartic Acid Endopeptidases; Endothelin-1; Endothelin-Converting Enzymes; Endothelium, Vascular; Female; Humans; Metalloendopeptidases; Pre-Eclampsia; Pregnancy

The aim of this study was to clarify the time course of plasma endothelin-1 levels and platelet counts after elective cesarean section in women with preeclampsia, and to investigate the relationship between them postoperatively.. We studied 20 patients with preeclampsia and 25 healthy pregnant women without preeclampsia who underwent cesarean section and 20 women without preeclampsia who had vaginal deliveries. The plasma endothelin-1 and platelet counts were measured serially after cesarean section.. 1) In patients with preeclampsia, plasma endothelin-1 levels peaked on postoperative day 0 (p<0.05), and remained high, then fell to the preoperative level from day 5. The concentration was lower in healthy pregnant women undergoing cesarean section than in patients with preeclampsia before surgery, but showed a gradual significant increase from postoperative day 0 to postoperative day 3 (p<0.05) before falling. The women who underwent vaginal delivery showed a peak level of endothelin-1 on the day of delivery but this fell rapidly between day 3. 2) Women with preeclampsia showed a negative correlation between plasma endothelin-1 levels and platelet counts after cesarean section (r=0.46, p<0.01), while women without preeclampsia undergoing cesarean and vaginal deliveries did not.. Endothelin-1 production is stimulated after cesarean section, which is paralleled with postpartal thrombocytopenia only in patients with preeclampsia.

Topics: Adult; Cesarean Section; Elective Surgical Procedures; Endothelin-1; Female; Humans; Platelet Count; Pre-Eclampsia; Pregnancy; Thrombocytopenia

The major pathophysiologic changes observed in preeclampsia suggest that endothelial cell dysfunction plays an important role in this disorder. The pathway mediating endothelial cell layer dysfunction is unknown. The concentration of endothelin-1 (ET-1), a potent mammalian vasoconstrictor peptide produced by the vascular endothelium, has been observed to be significantly increased in preeclampsia. In this study, we determined the in vitro effect of endothelin-1 on glutathione and lipid peroxide levels and on the secretion of vasoactive substances by human umbilical vein endothelial cells (HUVECs).. Human umbilical vein endothelial cells were incubated for 24 h in the presence of different concentrations of ET-1 (0-1000 pmol L(-1)), which were shown in an earlier experiment to have no effects on vitality and proliferation rate of HUVECs. The levels of glutathione (GSH) and lipid peroxides (LPO) were measured in endothelial cell lysates. For the measurement of vasoactive substances, levels of nitric oxide (NO), prostacyclin (PGI2) and thromboxane A2 (TXA2) were measured in endothelial cell supernatants.. At lower concentrations (5-50 pmol L(-1)), ET-1 increases the intracellular content of LPO, stimulates the secretion of TXA2, but inhibits the secretion of PGI2 in endothelial cells compared with control cells. At higher concentrations (100-1000 pmol L(-1)), ET-1 increases the intracellular content of GSH, but results in a decrease of LPO, and increase of PGI2, back to control levels. ET-1 has no effect on NO secretion.. These findings demonstrate that at concentrations corresponding to values in plasma from preeclamptic women, ET-1 induces oxidative stress and results in altered secretion of vasoactive substances in human endothelial cells. We conclude that ET-1 may participate in the pathway leading to endothelial cell dysfunction seen in preeclampsia.

Topics: Cells, Cultured; Dose-Response Relationship, Drug; Endothelin-1; Endothelium, Vascular; Epoprostenol; Female; Glutathione; Humans; Intracellular Fluid; Lipid Peroxides; Nitric Oxide; Pre-Eclampsia; Pregnancy; Thromboxane A2; Umbilical Veins

Pre-eclampsia complicates approximately 5-7% of pregnancies and it may be deleterious to both maternal and fetal health. In a prospective study, we investigated plasma endothelin (ET)-1 concentration within the 24th and 36th gestational week in non-smoking pregnant women. Thirty women fulfilled the criteria for the diagnosis of pre-eclampsia according to the American College of Obstetricians and Gynaecologists: de novo arterial hypertension after the 20th gestational week in at least two separate measurements and proteinuria of more than 300 mg/l in a random specimen. For comparison, we analysed blood samples from 125 non-pre-eclamptic pregnant women. ET-1 concentrations were higher in pre-eclamptic pregnancies at both time points (mean+/-S.D.: 1.07+/-2.00 versus 0.54+/-0.56 pg/ml, P=0.045 at 24th week; 0.75+/-1.20 versus 0.44+/-0.45 pg/ml, P=0.023 at 36th week). Receiver operating characteristic (ROC) curves revealed a significant interaction between ET-1 plasma concentrations at the 36th week and the diagnosis of pre-eclampsia [area under the curve (AUC)+/-S.E.M.: 0.657+/-0.049, P=0.008] and a cut-off value at 0.30 pg/ml. Multivariate analysis showed a 4.6-fold higher chance (95% confidence interval: 1.7-12.1, P=0.002) for the diagnosis of pre-eclampsia in pregnant women with ET-1 plasma concentration higher than 0.30 pg/ml at the 36th week. Interaction between ET-1 plasma concentration at the 24th week and diagnosis of pre-eclampsia was not significant in ROC curve analysis (AUC+/-S.E.M.: 0.594+/-0.071, P=0.278). Interestingly, we found a strong positive correlation between ET-1 concentration in the 24th and 36th week in linear regression analysis in pre-eclamptic (r=0.99, P<0.001) and non-pre-eclamptic pregnancies (r=0.61, P<0.001) with a slightly, non-significant decrease from the 24th to 36th week (for group means see above), indicating individual plasma ET-1 levels even in non-pre-eclamptic pregnancies. Linear regression analysis showed no correlation between blood pressure or urine protein excretion and ET-1 plasma concentration in non-pre-eclamptic pregnant women. In conclusion, our prospective study indicates that the ET system is, in contrast to most other forms of human hypertension, activated in pre-eclamptic pregnant women.

Topics: Adult; Biomarkers; Case-Control Studies; Endothelin-1; Female; Humans; Linear Models; Pre-Eclampsia; Pregnancy; Pregnancy Trimester, Second; Pregnancy Trimester, Third; Prospective Studies; Proteinuria; ROC Curve

The aim of this study was to evaluate the relationship between the vascular resistance in uterine arteries and the maternal release of adenosine and endothelin-1 in twin gestations with and without preeclampsia. Uterine artery Doppler velocimetry and maternal arterial blood sampling were performed in 14 women with normal singleton gestation, nine women with singleton gestation with preeclampsia, eight women with dichorionic twin gestation without preeclampsia and six women with dichorionic twin gestation with preeclampsia at 28-34 weeks' gestation. In normal singleton gestations, the average maternal uterine arteries pulsatility index (PI), plasma adenosine and endothelin-1 levels were 0.64+/-0.07, 0.34+/-0.11 micromol/l and 1.29+/-0.31 pg/ml, respectively. In preeclamptic singleton gestations, increased vascular resistance in the uterine arteries (PI: 0.85+/-0.14, P<0.05) and the elevation of maternal arterial plasma adenosine (0.48+/-0.14 micromol/l, P<0.05) and endothelin-1 levels (1.91+/-0.55 pg/ml, P<0.05) were observed. In the normal twin gestation group, the average maternal vascular resistance of the uterine arteries (PI: 0.55+/-0.09) was lower than that in the normal singleton gestation group, while the average plasma adenosine levels (0.47+/-0.12 micromol/l) were higher than that in normal singleton gestation. On the other hand, significant increased plasma endothelin-1 concentrations (1.87+/-0.42 pg/ml) were observed in the preeclamptic twin gestation groups without changes in plasma adenosine levels or vascular resistance of uterine arteries. Our results indicate the presence of different mechanisms for the pathogenesis of preeclampsia between twin and singleton gestations.

Topics: Adenosine; Adult; Arteries; Endothelin-1; Female; Humans; Pre-Eclampsia; Pregnancy; Pregnancy, Multiple; Reference Values; Twins; Uterus; Vascular Resistance

Plasma endothelin-1 activity was measured by radioimmunoassay in 24 normotensive non-pregnant women and in 24 normotensive pregnant, 24-aproteinuric hypertensive and 24 pre-eclamptic women. Endothelin-1 activity was increased in the pre-eclamptic group (2.7 +/- 06 pg/ml) compared to the normotensive non-pregnant (1.0 +/- 0.8 pg/ml; P < 0.0001), normotensive pregnant (1.2 +/- 0.4 pg/ml; P < 0.0001) group and the aproteinuric hypertensive group (1.4 +/- 0.7 pg/ml; P < 0.0001). There was no difference in endothelin-1 activity between the normotensive non-pregnant and normotensive pregnant group (1.0 +/- 0.8 vs. 1.2 +/- 0.4 pg/ml; P = 0.3). However, there was a difference between the aproteinuric hypertensive group (1.4 +/- 0.7 pg/ml) and both the normotensive nonpregnant (1.0 +/- 0.8 pg/ml; P < 0.01) and the normotensive pregnant group (1.2 +/- 0.4 pg/ml; P < 0.06). The birth weight in the pre-eclamptic group (2.48 +/- 0.61 kg) was significantly lower than that of the normotensive pregnant group (2.85 +/- 0.33 kg; P < 0.001) and the aproteinuric hypertensive group (2.99 +/- 0.46 kg; P < 0.001). In addition, there was no difference in birth weight between the normotensive pregnant group and aproteinuric hypertensive group (2.85 +/- 0.33 vs. 2.99 +/- 0.46 kg; P = 0.3). A significant Pearson's correlation of plasma endothelin-l versus birth weight in the pre-eclamptic group was obtained (r = 0.64; P < 0.0001). Endothelin-1 activity is increased with pre-eclampsia in black African women with pre-eclampsia. The results of our study also suggests an ethnic difference in plasma endothelin-1 activity when compared to result of studies carried out in Caucasian women with hypertensive disorders of pregnancy.

Topics: Adult; Endothelin-1; Female; Humans; Hypertension; Pre-Eclampsia; Pregnancy; Pregnancy Complications, Cardiovascular

Preeclampsia is characterized by vasospasm, multiple organ hypoperfusion and endothelial cell damage. Many of its signs and symptoms can be explained by an imbalance in the vasomotor tone-regulating factors, including nitric oxide (NO) and endothelin-1 (ET-1).. Plasma samples of 59 women (20 healthy nonpregnant (NP), 20 normotensive pregnant (NTP) and 19 preeclamptic pregnant (PEP) women) were investigated by means of nitrite (NO(2)(-))/nitrate (NO(3)(-)) (two end products of nitric oxide metabolism) and endothelin-1 values.. PEP, when compared with NP and NTP, showed a significant increase in the plasma nitrite/nitrate and endothelin-1 concentrations. There was a weak but significant correlation between the nitrite/nitrate and endothelin-1 concentrations in the NP and NTP groups (r(1)=0.46, P<0.05, and r(2)=0.38, P<0.05, respectively) which probably revealed the balance between these vasoactive factors. In PEP, no significant correlation between nitrite/nitrate and endothelin-1 was found. Increased nitric oxide production could be the compensation against the vasoconstriction and hypertension in preeclampsia.. A lack of correlation between nitrite/nitrate and endothelin-1 probably indicates that in preeclampsia, a primary defense mechanism of the compensatory nitric oxide may be lost.

Topics: Adult; Endothelin-1; Female; Humans; Nitrates; Nitric Oxide; Nitrites; Pre-Eclampsia; Pregnancy; Reference Values

To investigate whether the human mast cell chymase-endothelin-1(1-31) system was present in human myometrium, chorion and umbilical cord in normal pregnancy.. Myometrium, placenta and umbilical cord were obtained from five normal pregnant women and 10 with preeclampsia. Each tissue was stained with antibodies against hMC and ET-1(1-31).. Routine cells were located mainly around vessels. The number of hMC-positive cells and production of ET-1(1-31) were significantly higher in myometrium from patients with severe preeclampsia compared to those from normal pregnant women. In contrast, their numbers were significantly lower in placenta and umbilical cord in patients with severe preeclampsia.. These results suggest that the hMC-ET-1(1-31) system is active in normal pregnancy. Overproduction of hMC and ET-1(1-31) in the myometrium may be involved in the pathogenesis of severe preeclampsia, and in such cases some defense mechanism may operate in the fetus to cope with the pathological effect of the hMC-ET-1(1-31) system.

Topics: Chymases; Endothelin-1; Female; Humans; Mast Cells; Myometrium; Placenta; Pre-Eclampsia; Pregnancy; Reference Values; Serine Endopeptidases; Umbilical Cord

The objective of this study is to compare the serum levels of fibronectin, nitric oxide (NO), cyclic guanosine-monophosphate, endothelin-1, and 6-keto-prostaglandin-F 1alpha in women with and without preeclampsia before and after delivery.. We studied 20 singleton pregnancies complicated by preeclampsia, and 20 women undergoing elective cesarean delivery were selected as controls. The normalization of circulating concentrations of maternal plasma NO, cyclic guanosine-monophosphate, fibronectin, endothelin-1, thromboxane-B 2 and renin, and urinary 6-keto-prostaglandin-F 1alpha after delivery was evaluated.. Mean systolic and diastolic blood pressure (BP) in the puerperium of preeclamptic women remained high after discharge from hospital, and only circulating fibronectin levels were found to be elevated in affected women at the end of hospital stay 5 days after delivery. Normalization of the imbalance in vasoactive substances and renal impairment in preeclampsia occur more rapidly than the patient's clinical recovery, within 2-3 days postpartum.. Slow normalization of circulating fibronectin concentrations reflects slow recovery of endothelial damage in preeclampsia, which may play a major role in maintaining high BP in the puerperium. Plasma levels of endothelin-1 declined to normal levels by the third postpartum day and the finding is consistent with the hypothesis that endothelin-1 is not the major vasoconstrictor in the pathophysiology of preeclampsia.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Biomarkers; Cesarean Section; Cyclic GMP; Endothelin-1; Endothelium, Vascular; Female; Fibronectins; Humans; Longitudinal Studies; Nitric Oxide; Postpartum Period; Pre-Eclampsia; Pregnancy; Pregnancy Complications, Cardiovascular; Time Factors; Vasoconstrictor Agents; Vasodilator Agents

The pathogenesis of pre-eclampsia is still unclear. Placental hypoperfusion, which precedes the maternal manifestations of pre-eclampsia, could be due to some vasoconstrictor factor/s like endothelin-1. The aim of the study therefore was to estimate the levels of endothelin-1 in feto-placental tissue homogenates from normotensive pregnant women and women with pre-eclampsia.. Fresh, vaginally delivered placentae from ten normotensive pregnant women and nine women with pre-eclampsia were carefully dissected and 4 gm each of amnion, chorion laeve, placental plate chorion, fetal placenta (fetal surface of the placenta) and maternal placenta (surface of the placenta attached to the uterine wall) were obtained. These tissues were then thoroughly washed in a 0.5 M phosphate buffer, pH 7.5, at room temperature and then individually homogenized for one minute in 4 ml of the same buffer. After centrifugation the supernatant was removed. The pellet was re-suspended in buffer, re-homogenized and then centrifuged. The supernatant was removed and the procedure was repeated once again and the three supernatants of each tissue were pooled. Endothelin-1 was estimated by RIA. All results are presented as mean+/-SEM. Statistical analysis was performed using students 't' test for unpaired samples and a 'p' value of <0.05 was considered significant.. In tissues from normotensive pregnant women, no significant differences were evident in endothelin-1 concentrations in the chorion laeve, fetal placenta and maternal placenta but were significantly higher than those in the amnion and placental plate chorion (p<0.01). In tissues from pre-eclamptic women, no significant differences were evident between endothelin-1 concentrations in the chorion laeve, placental plate chorion and fetal placenta. Mean endothelin-1 concentration in the amnion and maternal placenta were significantly lower than those in chorion laeve, placental plate chorion and fetal placenta (p<0.01). Endothelin-1 concentrations were significantly higher in the amnion, chorion laeve, placental plate chorion and fetal placenta from women with pre-eclampsia when compared to tissues from normotensive pregnant women (p<0.01).. Endothelin-1 levels were significantly higher in the placental tissues from women with pre-eclampsia. Endothelin-1, being a powerful vasoconstrictor, could cause significant vasoconstriction in the placental vasculature, and alterations in endothelin-1 levels in placental vasculature may therefore have a role in the pathogenesis of pre-eclampsia.

Topics: Adult; Amnion; Decidua; Endothelin-1; Female; Fetus; Humans; Placenta; Pre-Eclampsia; Pregnancy

Increased vascular sensitivity to vasoconstrictors, such as angiotensin II and epinephrine, is observed in preeclampsia (PE). Recently, it was suggested that abnormal endothelial function might contribute to the pathophysiologic changes in PE. We investigated vasoconstrictor (angiotensin II and epinephrine)-induced endothelin-1 (ET-1) release from human umbilical vein endothelial cells incubated with sera from women with PE compared with normotensive pregnant and nonpregnant women. Moreover, inositol 1,4,5-trisphosphate production and endothelin-converting enzyme (ECE) expression in human umbilical vein endothelial cells were also evaluated. There were no significant differences in ET-1 release without vasoconstrictors among the three groups (nonpregnant, normotensive pregnant, and PE). No significant differences in basal inositol 1,4,5-trisphosphate production and ECE expression without vasoconstrictors were detected among the three groups. Vasoconstrictor-induced ET-1 release was significantly increased by PE sera. No significant difference was detected in vasoconstrictor-induced inositol 1,4,5-trisphosphate production among the three groups. However, ECE expression after incubation with vasoconstrictor was significantly increased by PE sera. Our results suggest that ET-1 release from endothelial cells may contribute to the increased vascular sensitivity to vasoconstrictors observed in PE, and that vasoconstrictor-induced ET-1 release may be related to enhanced ECE expression.

Topics: Adult; Angiotensin II; Aspartic Acid Endopeptidases; Blood Physiological Phenomena; Cells, Cultured; Endothelin-1; Endothelin-Converting Enzymes; Endothelium, Vascular; Epinephrine; Female; Humans; Inositol 1,4,5-Trisphosphate; Metalloendopeptidases; Pre-Eclampsia; Pregnancy; Reference Values; Vasoconstrictor Agents

Both nitric oxide (NO) and endothelin-1 (ET-1) are important mediators in the regulation of vascular tone during pregnancy and preeclampsia. This study was designed to investigate the ET-1-induced hypotensive effect in late pregnant rats (P) and in NO-deprived hypertensive pregnant rats (TP), a model of preeclampsia. From day 13 of pregnancy Wistar rats were fed a control or an N(omega)-nitro-L-arginine-enriched diet. On gestational day 20, mean arterial pressure (MAP +/- SEM, in mm Hg) and heart rate (HR) were measured with a carotid catheter in anesthetized rats after a bolus intravenous injection of several agonists and antagonists. After 7 days of chronic NO synthase inhibition, there was a significant increase in MAP (+45 +/- 3.9, P < .01) and 24-h urinary nitrate excretion was significantly decreased (P < .05). ET-1 bolus injection (0.1 nmol/kg) was rapidly followed by a significant decrease in MAP and a slight delayed increase, with no change in HR. The magnitude of the decrease had significantly dropped off in P (-30 +/- 2.2) as compared to that in TP (-46 +/- 5.1) and in virgin rats (-51 +/- 6.3) (P < .05). In P and TP, in vivo depressor effect was also obtained with sarafotoxin S6c, a specific ETB agonist, and blocked by the specific ETB antagonist BQ-788. After inhibition of cyclooxygenase with acetylsalicylic acid, the ET-1-induced hypotension was not modified either in P or in TP. In conclusion, the present data highlight an enhanced ETB receptor mediated hypotensive effect of ET-1 in anesthetized TP as compared to P. The magnitude of the hypotensive effect of ET-1 observed in TP is of the same order as that in virgin rats and neither NO nor vasodilator prostaglandins seem to be involved in TP. The enhanced hypotensive effect of ET-1 could be a beneficial counter-balancing mechanism in this rat model of preeclamptic pathology where an increased sensitivity to vasoconstrictor agents is generally described.

Topics: Animals; Blood Pressure; Endothelin-1; Female; Hypotension; Nitric Oxide; Pre-Eclampsia; Pregnancy; Rats; Rats, Wistar; Receptor, Endothelin B; Receptors, Endothelin

We have suggested that a novel endothelin-1 with 31 amino acids [ET-1 (1-31)] plays an important role in fetal circulation, owing to a strong contractile activity on the umbilical artery. To clarify the pathophysiological significance of ET-1 (1-31) in the development of severe preeclampsia, its contractile activities on human umbilical arteries and uterine smooth muscle from patients with preeclampsia were studied. The contraction by ET-1 (1-31) was stronger in uterine smooth muscle of the patients with severe preeclampsia than that of normal subjects. On the contrary, the constriction of umbilical artery of the patients with eclampsia was significantly weaker than that of normal pregnant women. The stronger contraction of myometrium by ET-1 (1-31) in patients with severe preeclampsia observed for the first time in the present study suggests that ET-1 (1-31) might be involved in the development of preeclampsia.

Topics: Case-Control Studies; Dose-Response Relationship, Drug; Endothelin-1; Endothelins; Female; Humans; Muscle Contraction; Muscle, Smooth; Peptide Fragments; Pre-Eclampsia; Pregnancy; Umbilical Cord; Uterus

This study examined the frequency of the Lys198Asn polymorphism in the endothelin-1 (ET-1) gene in women with pre-eclampsia and normal pregnancy; and its contribution to levels of plasma ET-1 and blood pressure.. This was a retrospective study examining the frequency of the ET-1 Lys198Asn polymorphism in 72 proteinuric pre-eclamptics and 81 normal pregnant women. Height, weight, blood pressure and plasma ET-1 were measured antenatally and at 6 weeks post-partum. Using specific mutagenic primers, the frequency of the G/G (normal), G/T heterozygote and T/T (mutant) genotypes of the Lys198Asn polymorphism were examined.. The polymorphism was not associated with pre-eclampsia. However, in the combined pregnant groups after correction for BMI and group, a significant effect of the T-allele (T/T,G/T) on systolic blood pressure was found (121 +/- 1.5 mmHg compared with 116 +/- 1.3 mmHg in the G/G homozygotes). A significant interaction was found between the T-allele and pregnancy in determining systolic blood pressure, so that the effect was no longer seen post-partum. Pregnant women with the T/T genotype had significantly elevated plasma ET-1 levels 5.8 pg/ml [confidence interval (CI) 3.7-9.1] compared with 3.1 pg/ml (CI 2.6-3.8) in the G/T heterozygotes and 3.6 pg/ml (CI 3.0-4.1) in the normal G/G homozygotes.. The Lys198Asn polymorphism does not directly contribute to the incidence of pre-eclampsia. However, the association of the T-allele with raised blood pressure and the T/T genotype with increased plasma ET-1 levels suggest that this polymorphism may interact with other genes or environmental factors to sensitize pregnant women to develop pre-eclampsia.

Topics: Adult; Alleles; Amino Acid Sequence; Blood Pressure; Endothelin-1; Female; Gene Frequency; Genotype; Humans; Polymorphism, Genetic; Postpartum Period; Pre-Eclampsia; Pregnancy; Reference Values

The aim of this study was to investigate the relationship between plasma endothelin 1 (ET-1) levels and T helper (Th)-1:Th2 cell immunity in women with preeclampsia. The percentage of Th1 and Th2 cells and the Th1:Th2 cell ratios in peripheral blood from 11 normal pregnant women and 11 patients with preeclampsia at 29-34 weeks of gestation were calculated using flow cytometry. The plasma ET-1 level was also determined using a modified radioimmunoassay. The plasma ET-1 concentrations and the Th1:Th2 cell ratios in normal pregnancies were significantly lower than those in patients with preeclampsia. Negative correlations were found between plasma ET-1 levels and Th2 cells in both the preeclamptic pregnancy groups and in the normal pregnant women. Our results indicate that elevated ET-1 levels are associated with a Th1:Th2 imbalance in preeclampsia.

Topics: Adult; Birth Weight; Endothelin-1; Female; Flow Cytometry; Gestational Age; Humans; Infant, Newborn; Lymphocyte Count; Pre-Eclampsia; Pregnancy; Th1 Cells; Th2 Cells

To determine the in vitro effect of serum from preeclamptic patients on the proliferation, viability and secretion of vasoactive substances by human umbilical vein endothelial cells (HUVEC).. HUVEC were incubated for 24h with sera from 16 preeclamptic, 19 healthy pregnant and 8 healthy nonpregnant women. Proliferation rates were determined by cell counting and vitality by trypan blue staining. The vasoactive substances, 6-keto-prostaglandin F(1alpha), nitrite and nitrate, and endothelin-1 (ET-1) were measured in endothelial cell supernatants.. The preeclamptic serum had no effect on cell proliferation or vitality compared with control sera. It induced more HUVEC production of ET-1, but not of prostacyclin (PGI2) or nitric oxide compared with control serum.. Preeclamptic serum appears to contain a factor(s) that specifically stimulates ET-1 secretion from HUVEC without altering cell growth or vitality.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Blood; Cell Division; Cells, Cultured; Culture Media; Endothelin-1; Endothelium, Vascular; Female; Humans; Nitrates; Nitric Oxide; Nitrites; Pre-Eclampsia; Pregnancy; Umbilical Veins

Oxidative stress might be the reason for endothelial dysfunction in preeclampsia. The glutathione-peroxidase system is one of the primary antioxidants in the endothelium. We tested the effect of oxidative stress by reduction of glutathione availability on the secretion of vasoactive substances in endothelial cells.. Endothelial cells in culture were incubated with different concentrations of buthionine-[S,R]-sulfoximine (BSO) or 1-chloro-2,4-dinitrobenzene (CDNB), both leading to a reduced intracellular availability of glutathione. The secretion of the vasoactive substances nitric oxide (NO), endothelin-I (ET-1), and prostacyclin (PGI2) was measured with respect to vitality and proliferation rate of the endothelial cells in culture.. Effect of oxidative stress on the secretion of vasoactive substances from endothelial cells.. The oxidants CDNB and BSO have (in concentrations before evidence of cytotoxicity) a stimulating effect on the production of PGI2, they inhibit NO availability, and they do not significantly interfere with ET-1 production. Conclusion Oxidative stress in vitro induces an imbalance in the secretion of NO, ET-1, and PGI2 in endothelial cells.

Topics: Biological Availability; Cells, Cultured; Endothelin-1; Endothelium, Vascular; Epoprostenol; Female; Glutathione; Humans; Nitric Oxide; Oxidative Stress; Pre-Eclampsia; Pregnancy; Umbilical Veins

The aim of this study was to examine the distribution of endothelin-1 (ET-1) in the human placenta at different gestational ages and to determine whether differences in ET-1 immunoreactivity occurred in preeclamptic compared with uncomplicated pregnancies.. Localization of ET-1 was investigated by the immunoperoxidase technique in first-trimester, second-trimester, and term human placentas from normal pregnancies and in placentas from preeclamptic pregnancies.. In normal placentas from all gestational ages studied, endothelin-1 immunoreactivity (ET-1 IR) was specifically detected in the endothelium of the fetal vessels and in the syncytiotrophoblast. ET-1 IR was also expressed by the villous cytotrophoblast of first- and second-trimester normal placentas. The extravillous cytotrophoblast of the basal and chorionic plates also exhibited ET-1 IR, but with varying degrees of intensity. In preeclamptic placentas, the expression of ET-1 IR was uneven with a negative staining in all placentas from pregnancies between the 29th and 32nd weeks of gestation. The expression of ET-1 IR was most intense in some syncytiotrophoblast tissue in the terminal villi after the 33rd week of gestation. In placentas from preeclamptic pregnancies between the 35th and the 36th weeks of gestation, strong ET-1 IR expression was evident in the endothelium of fetal vessels and in the syncytiotrophoblast. Regardless of gestational age, ET-1 IR was also observed in the extravillous cytotrophoblast of the basal and chorionic plates of preeclamptic placentas.. This study demonstrates that ET-1 IR is widely distributed in the human placenta and provides further evidence to support the concept that ET-1 plays an important role as a modulator of vascular tone in the uteroplacental and fetoplacental units and may participate in the pathogenesis of preeclampsia.

Topics: Endothelin-1; Female; Gestational Age; Humans; Immunoenzyme Techniques; Immunohistochemistry; Placenta; Pre-Eclampsia; Pregnancy; Pregnancy Trimester, First; Pregnancy Trimester, Second; Pregnancy Trimester, Third

We attempted to investigate the role of nitric oxide(NO) in pathogenesis of pregnancy-induced hypertension(PIH).. No-nitro-L-arginine-methyl ester(L-NAME) was used to inhibit nitric oxide synthase(NOS) in pregnant rats. Indices including blood pressure, urine protein concentration, pup weight, serum NO level and plasma ET-1 level were measured. Nitroglycerin, a nitric oxide donor, was used to observe its impact on the effect of L-NAME at the same time.. Infusion of L-NAME elevated blood pressure, increased urine protein concentration, decreased pup weight, decreased serum NO level and raised plasma ET-1 level(P < 0.01, respectively); However in the L-NAME-treated animals nitroglycerin significantly lowered blood pressure, decreased urine protein concentration, increased pup weight, increased serum NO level and decreased plasma ET-1 level(P < 0.01, respectively).. 1. Infusion of L-NAME, an inhibitor of NOS, causes decreased serum NO level and some signs similar to preeclampsia such as hypertension, proteinuria and intrauterine growth retardation(IUGR). Nitroglycerin can reverse the lesions induced by the treatment of L-NAME. These findings indicate that reduced level of NO may be a factor responsible for PIH. 2. NO can decrease the plasma ET-1 level. NO may regulate the process of PIH via ET-1 pathway. It may be one mechanism for NO. 3. An useful animal model for PIH is provided to test novel therapeutic and preventive strategies.

Topics: Animals; Endothelin-1; Female; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Donors; Nitric Oxide Synthase; Nitroglycerin; Pre-Eclampsia; Pregnancy; Random Allocation; Rats; Rats, Sprague-Dawley

Topics: Adult; Cells, Cultured; Culture Media; Endothelin-1; Endothelium, Vascular; Female; Humans; Nitric Oxide; Plasma; Pre-Eclampsia; Pregnancy; Umbilical Veins

To determine whether increased first trimester plasma endothelin-1 and/or increased midtrimester mean arterial blood pressure detected in pregnant women who are free of symptoms can predict the subsequent development of pre-eclampsia.. Eighty pregnant women were successfully followed from 10 weeks gestation until delivery. Pre-eclampsia and eclampsia developed in 29 and 2 women, respectively, whereas 49 women remained normotensive. Plasma endothelin-1 was determined in the first trimester (10-12 weeks gestation) by a competitive radioimmunoassay.. First trimester plasma endothelin-1 levels in pregnant women who subsequently developed mild, severe pre-eclampsia and eclampsia were significantly higher than those of pregnant women who remained normotensive. The release of endothelin-1 increases with the severity of the disease, age, body mass index and mean arterial blood pressure. The predictive values of plasma endothelin-1 for pre-eclampsia were: sensitivity 96.8%, specificity 51%, positive predictive value 55.5% and negative predictive value 91%, whereas those of MAP were 48.4, 45, 35.7 and 58%, respectively.. Determination of first trimester plasma endothelin level may be a valuable marker to identify 55.5% of individuals at high risk of developing pre-eclampsia, if combined with midtrimester MAP, the positive predictive value increases to 68.2%.

Topics: Adolescent; Adult; Blood Pressure; Body Mass Index; Endothelin-1; Female; Humans; Pre-Eclampsia; Predictive Value of Tests; Pregnancy; Pregnancy Trimester, First; ROC Curve; Sensitivity and Specificity

Preeclampsia is a mainly vascular disease of pregnancy, probably caused by an imbalance between vasodilator and vasoconstrictor agents that results in generalized vasospasm and poor perfusion in many organs. Among these factors, endothelin-1 (ET-1), a potent vasoconstrictor, is highly increased in preeclamptic women, while nitric oxide (NO), a vasodilator of human utero-placental arteries, is reduced in the same patients. The present study was designed to investigate the interactions between ET-1 and the NO system in the feto-placental unit; to this purpose we also examined the messenger ribonucleic acid (mRNA) expression of ET-1, inducible NO synthase (iNOS), and endothelial NOS (eNOS) in human cultured placental trophoblastic cells obtained from preeclamptic (PE) and normotensive (NT) pregnancies. We also studied whether exogenous ET-1 may affect the expression of iNOS and eNOS in human placental trophoblastic cells. Interestingly, by Northern blot analysis we observed an increased ET-1 mRNA expression level in PE trophoblastic cells compared to NT trophoblastic cells. Furthermore, exogenous ET-1 (10(-7) mol/L) was able to up-regulate its own mRNA expression in both NT and PE trophoblastic cells. iNOS and eNOS mRNA expression was then detected, by semiquantitative PCR, in both NT and PE trophoblastic cells. PE trophoblastic cells expressed lower iNOS mRNA levels compared with NT pregnancies. On the contrary, eNOS mRNA expression was higher in PE trophoblastic cells than in NT cells. Moreover, in the presence of ET-1 we observed a decrease in iNOS and an increase in eNOS mRNA expression levels in both NT and PE trophoblastic cells compared with the respective untreated cells. In conclusion, we demonstrate that ET-1 expression is increased in PE cells, whereas iNOS, which represents the main source of NO synthesis, is decreased; conversely, eNOS expression is increased. Finally, ET-1 is able to influence its own as well as NOS isoform expression in normal and PE trophoblastic cultured cells. These findings suggest the existence of a functional relationships between ET(s) and NOS isoforms that could constitute the biological mechanism leading to the reduced placental blood flow and increased resistance to flow in the feto-maternal circulation, which are characteristic of the pathophysiology of preeclampsia.

Topics: Adult; Birth Weight; Endothelin-1; Female; Gestational Age; Humans; Infant, Newborn; Isoenzymes; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; Placenta; Pre-Eclampsia; Pregnancy; Proteinuria; Reference Values; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Transcription, Genetic

Recently it was suggested that abnormal endothelial function may contribute to the pathophysiological changes observed in preeclampsia (PE). Both nitric oxide (NO) and endothelin-1 (ET-1) are vasoactive substances produced by endothelial cells. NO is a vasodilator and has been believed to be decreased in PE. ET-1 is a vasoconstrictor and has been reported to be increased in PE. We simultaneously measured NO metabolites and ET-1 in sera from women with PE and investigated the correlation of NO and ET-1 concentrations. We obtained serum samples from 11 healthy nonpregnant (NP) women, 16 normotensive pregnant (NTP) women and 17 women with PE. In this study, the serum ET-1 level was assayed by the ET-1 RIA system, and serum NO metabolites were assayed by measuring nitrite (NO2-) and nitrate (NO3-) simultaneously in an HPLC-Griess reaction system. There was a significant correlation between NOx (nitrite + nitrate) and ET-1 in sera from all 44 women (NP, NTP and PE groups) (p<0.001). Nitrite and ET- in sera from each group were not significantly correlated. Nitrate and ET-1 in sera from the NP and NTP groups did not significantly correlate. However, there was a significant correlation between nitrate and ET-1 in sera from the PE group (p<0.05). The serum ET-1 and nitrate concentration in the PE group was significantly higher than in the NP and NTP groups (p<0.05 and p<0.001. respectively). These findings suggest that increased production of nitrate in PE may contribute to homeostatic vasodilation against vasoconstriction caused by a higher ET-1 concentration.

Topics: Endothelin-1; Endothelium, Vascular; Female; Humans; Nitrates; Pre-Eclampsia; Pregnancy

The aim of the present study was to compare the mRNA expression of endothelin-1 (ET-1), ET-1 receptors ET(A) and ET(B) in myometrium and placenta obtained from biopsies collected from women with preeclampsia (n=10) or normal pregnant (n=12).. The mRNA levels of ET-1 ET(A) and ET(B) were determined using RT-PCR and expressed as arbitrary units after correction for control GAPDH gene mRNA levels.. The mRNA levels of ET-1 in myometrium and placenta were not altered in women with preeclampsia compared to normal pregnant. The mRNA expression of ET(A) was significantly reduced (p<0.05) in both placenta and myometrium from women with preeclampsia. The mRNA levels of ET(B) were similar in placentas from both preeclamptic and normal pregnant women, but higher in myometrium (p<0.05) from women with preeclampsia.. These results indicate that the higher levels of ET-1 seen in preeclamptic women do not depend on an altered mRNA transcription of ET-1. The significantly reduced mRNA expression of ET(A) receptor in myometrium and placenta in women with preeclampsia might represent downregulation of the receptors due to the increased levels of ET-1 in uteroplacental circulation in this disorder. Much more research is needed before the role of ET(B) receptors in preeclampsia can be clarified.

Topics: Adult; Endothelin-1; Female; Gene Expression; Humans; Myometrium; Placenta; Pre-Eclampsia; Pregnancy; Receptor, Endothelin A; Receptor, Endothelin B; Receptors, Endothelin; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger

To investigate the effect of neutrophil activation on pathogenesis of pre-eclampsia, neutrophil activation was examined by using flow cytometry to assess the CD11b expression and the levels of plasma endothelin-1 (ET-1) and serum NO2- were also measured by using non-equilibrium radioimmunoassay and by Griess assay in 29 pregnant women with pre-eclampsia and 31 normal pregnant women at third trimester. The expression of neutrophil CD11b was significantly elevated in women with pre-eclampsia as compared with that of normal pregnant women at third trimester. The mean fluorescence index of CD11b was 438.38 +/- 179.91 and 326.97 +/- 170.14 respectively (P < 0.05). The plasma ET-1 level and serum NO2- concentration in pre-eclampsic women (63.69 +/- 48.33 pg/ml and 20.03 +/- 4.77 mumol/L, respectively) were both significantly increased as compared with those in the normal pregnancy women (29.98 +/- 20.25 pg/ml and 15.47 +/- 5.47 mumol/L, respectively, P < 0.01). The neutrophil CD11b expression was significantly elevated in pre-eclampsia. The increased neutrophil activation may cause the damage of vascular endothelium and result in NO release compensatory increase in endothelial cells, suggesting that the neutrophil activation may play a key role in pathogenesis of pre-eclampsia.

Topics: Adult; Endothelin-1; Female; Humans; Macrophage-1 Antigen; Neutrophil Activation; Nitric Oxide; Pre-Eclampsia; Pregnancy

To compare plasma endothelin-1 (ET-1) concentrations in preterm neonates from pre-eclamptic and normal mothers; and to evaluate whether ET-1 has a role in altered arterial blood flow velocity.. Umbilical arterial blood and neonatal arterial blood were sampled on days 1 and 3 for gas analysis and measurement of plasma ET-1. Doppler ultrasonography of the middle cerebral, renal, and superior mesenteric arteries (SMA) was performed.. Neonates in the pre-eclampsia (n = 18) and control (n = 18) groups had mean (SD) gestational ages of 31.1 (2.5) weeks and 30.4 (2.1) weeks; their birth-weights were 1432 (SD 676) g and 1692 (SD 500) g, respectively. In the pre-eclampsia group mean umbilical arterial PO2 was lower--1.88 (0.75) kPa compared with 3.27 (1.41) kPa (p < 0.01)--and mean plasma ET-1 concentration was higher in the umbilical artery--40.6 (SD 15.0) compared with 30.5 (SD 13.8) pg/ml (p = 0.04) and day 1 blood--54.9 (35.0) pg/ml compared with 33.6 (14.6) pg/ml (p = 0.03). Middle cerebral artery peak systolic velocity was higher and SMA time averaged, peak systolic, and mean peak velocities were lower in the pre-eclampsia group. SMA time averaged velocity was inversely related to plasma ET-1 concentration.. The association between increased production of ET-1 and reduction in SMA time averaged velocity suggests a possible mechanism for hypoperfusion of the intestinal wall in neonates.

Topics: Blood Flow Velocity; Cerebral Arteries; Endothelin-1; Female; Fetal Hypoxia; Humans; Infant, Newborn; Infant, Premature; Mesenteric Artery, Superior; Oxygen; Pre-Eclampsia; Pregnancy; Prospective Studies; Ultrasonography, Doppler

To compare maternal and umbilical venous big endothelin (big ET) and endothelin-1 (ET-1) levels of pregnancies complicated by severe preeclampsia (PE) or HELLP-syndrome to those of a well-matched normotensive pregnant control group.. We measured plasma levels of ET-1 and big ET in 16 patients with severe PE and 14 patients with HELLP-syndrome by commercially available RIAs and compared them with those of well-matched normotensive pregnant controls. Additionally, the umbilical venous ET-1 and big ET levels were determined in 10 corresponding newborns.. The plasma concentrations of ET-1 and big ET were significantly higher in patients with severe PE and especially in women with HELLP-syndrome when-compared with controls. The molar ratios of big ET to ET-1 were significantly lower in the two study groups. The levels of ET-1 and big ET were higher in umbilical venous plasma than in maternal plasma, but there were no significant differences in the umbilical venous concentrations between normotensive and by severe PE or HELLP-syndrome complicated pregnancies.. These findings suggest that ET-1 may be considered as a marker of endothelial injury in by severe preeclampsia or HELLP-syndrome complicated pregnancies. The increase of the ET-1 plasma levels may be due, at least in part, to changes in the conversion of big ET to ET-1 by the endothelin-converting enzyme.

Topics: Adult; Endothelin-1; Endothelins; Female; Fetal Blood; HELLP Syndrome; Humans; Immunoenzyme Techniques; Maternal Age; Pre-Eclampsia; Pregnancy; Pregnancy, High-Risk; Protein Precursors; Sensitivity and Specificity

This study aimed to identify those factors in the non-pregnant state that distinguished women who developed pre-eclampsia from those who had normotensive pregnancies.. This was a retrospective analysis of anthropometry, blood pressure, biochemical and haematological variables in 62 women with pre-eclampsia and 84 normotensive pregnant women who took part in studies of the pathophysiology of pre-eclampsia. Pregnant volunteers were seen, after admission to hospital or in the outpatient clinic, and followed-up at 6 weeks and 6 months post-partum in the outpatient clinic or their home. Participants Proteinuric pre-eclampsia was defined as blood pressure > or = 140/90 mmHg with proteinuria of at least 300 mg/24 h after 20 weeks gestation, in women with no history of hypertension and whose blood pressure returned to normal levels by 6 months post-partum. Normotensive pregnancy was defined as blood pressure < 130/90 mmHg without proteinuria.. The primary outcome measures were blood pressure, body mass index (BMI), triglycerides, total cholesterol, low density lipoprotein (LDL) and high density lipoprotein cholesterol and markers of severity of pre-eclampsia.. Regardless of parity, women with pre-eclampsia had elevated BMI before, during and after pregnancy compared with women who had normotensive pregnancies. Triglycerides were significantly elevated in women who had pre-eclampsia both before and after delivery, while total and LDL cholesterol were elevated significantly at both visits after delivery. Systolic and diastolic blood pressure, which by definition were elevated antepartum in women with pre-eclampsia, remained higher at post-partum visits compared with women who had normotensive pregnancies. Women with pre-eclampsia reported a greatly increased frequency of both maternal hypertension and pre-eclampsia. Markers of severity of pre-eclampsia, which normalized by 6 months postpartum, included plasma creatinine, uric acid, albumin, endothelin 1 and urinary protein, 2,3, dinor-6-keto-PGF1alpha, blood platelet and neutrophil counts.. The relative elevation of blood pressure, BMI and lipids in the non-pregnant state are features of the metabolic syndrome and may be important sensitizing factors contributing to the pathogenesis of pre-eclampsia. A familial predisposition to pre-eclampsia may operate partly through these mechanisms.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Blood Pressure; Body Mass Index; Causality; Creatinine; Endothelin-1; Female; Heart Rate; Humans; Hyperlipidemias; Hypertension; Lipids; Parity; Pre-Eclampsia; Pregnancy; Retrospective Studies; Serum Albumin; Uric Acid

In order to evaluate whether lipid abnormalities may contribute to endothelial dysfunction in pre-eclampsia, the present study examined the in vitro effects of very-low-density lipoprotein (VLDL), low-density lipoprotein (LDL) and high-density lipoprotein (HDL), isolated from women with pre-eclampsia and matched controls, on the endothelial synthesis of 6-oxo-prostaglandin F(1alpha) (6-oxo-PGF(1alpha); a metabolite of prostacyclin) and endothelin 1, and on the expression of nitric oxide synthase 3 (NOS3) mRNA. VLDL, LDL and HDL cholesterol were isolated from 20 pre-eclamptic and 20 age- and gestation-matched normal pregnant women. The lipoproteins (50 microgram/ml) and lipoprotein-free control plasma were incubated for 1, 3 and 6 h at 37 degrees C with a human umbilical endothelial cell line. The synthesis of 6-oxo-PGF(1alpha) and endothelin 1, and NOS3 mRNA expression, were measured at each time point. VLDL from pre-eclamptic women stimulated endothelial cell 6-oxo-PGF(1alpha) synthesis to a lesser extent than that from normal pregnant women (P<0.05). LDL from women with pre-eclampsia also stimulated 6-oxo-PGF(1alpha) synthesis to a lesser extent than LDL from normal pregnant women, but the effect was less sustained. The effect of HDL from women with pre-eclampsia on 6-oxo-PGF(1alpha) synthesis was similar to that of HDL from normal pregnant women. The pre-incubation levels of lipid peroxides in VLDL and LDL were not different between the normal pregnant and pre-eclamptic women, and cannot account for the decrease in 6-oxo-PGF(1alpha) synthesis. VLDL, LDL and HDL from women with pre-eclampsia did not affect endothelial cell synthesis of endothelin 1 or expression of NOS3 mRNA differently from lipoproteins from normal pregnant women. This study suggests that VLDL, and to a lesser extent LDL, from women with pre-eclampsia could potentially contribute to the reduced systemic 6-oxo-PGF(1alpha) synthesis observed in the pre-eclamptic syndrome.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Case-Control Studies; Cells, Cultured; Endothelin-1; Endothelium, Vascular; Female; Gene Expression; Humans; Lipoproteins, HDL; Lipoproteins, LDL; Lipoproteins, VLDL; Nitric Oxide Synthase; Nitric Oxide Synthase Type III; Polymerase Chain Reaction; Pre-Eclampsia; Pregnancy; RNA, Messenger; Statistics, Nonparametric; Time Factors

To investigate the role of endothelin (ET-1) in the pathogenesis of pregnancy induced hypertension (PIH).. In 70 cases of PIH the plasma concentration of ET-1 was measured by RIA, and the expressions of ET-1 and its mRNA in placental villus were determined by immunohistochemistry and in situ hybridization respectively. 30 normal pregnant women (NP) served as control group.. (1) The Plasma concentration of ET-1 was significantly higher in PIH than that in NP. There was a positive correlation between the plasma ET-1 level and mean arterial pressure in PIH. (2) The expressions of ET-1 and ET-1 mRNA were found in syncytiotrophoblast of placental villus and in the endothelium of fetal vessels. These positive signals were higher in PIH than in NP.. The injury of endothelium of fetal and placental blood vessels was one of the causes of PIH. The placenta may play an important role in the pathogenesis of PIH.

Topics: Adult; Chorionic Villi; Endothelin-1; Female; Humans; Pre-Eclampsia; Pregnancy; RNA, Messenger

To study the changes and clinical significance of plasma endothelin (ET-1) and calcitonin gene-related peptide (CGRP) levels in patients with pregnancy induced hypertension (PIH).. Plasma ET-1 and CGRP were studied by immunoradiological method in 60 patients with pregnancy induced hypertension (PIH) and 23 normal pregnant women and 20 normal non-pregnant women.. The levels of plasma ET-1 in patients with PIH were significantly higher than those in healthy pregnancies (P < 0.01). There was a positive correlation between the plasma ET-1 level and degree of PIH; the higher the ET-1 level, the severer the PIH. The levels of plasma CGRP in patients with moderate and severe PIH decreased significantly than those in healthy pregnancy. There was a negative correlation between the plasma CGRP level and ET-1 level.. The results suggest that plasma ET-1 and CGRP concentration could be used as indicators for the severity of PIH. CGRP may be one of the antagonists of ET-1 in the pathogenesis of PIH.

Topics: Adult; Calcitonin Gene-Related Peptide; Endothelin-1; Female; Humans; Pre-Eclampsia; Pregnancy

To study the role of tumor necrosis factor (TNF-alpha) in the pathogenesis of pregnancy induced hypertension (PIH).. Radioimmunoassay was used to measure the levels of TNF-alpha in 25 severe PIH patients and 25 normal pregnant women. Umbilical vein endothelial cells were cultured with TNF-alpha (500 U/ml) or without TNF-alpha. The concentration of endothelin-1 (ET-1), 6-ket-PGF1 alpha, nitrite (NO2-), expression of fibronectin(FN) and white blood cells adhesion to the surface of endothelial cells test were measured.. The levels of TNF-alpha in serum of severe PIH patients were significantly higher than that of normal pregnant women (P < 0.05). In endothelium culture supernatant with TNF-alpha group, synthesis of ET-1, NO2- and 6-ket-PGF1 alpha increased, expression of FN on the surface of endothelial cells decreased, white blood cells adhesion to endothelial cells increased. There was significant difference between TNF-alpha group and control group.. TNF-alpha may be involved in the pathogenesis of PIH.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Cells, Cultured; Endothelin-1; Endothelium, Vascular; Female; Humans; Infant, Newborn; Pre-Eclampsia; Pregnancy; Tumor Necrosis Factor-alpha; Umbilical Veins

To study the effect of the inhibition of nitric oxide(NO) synthesis on plasma endothelin (ET), prostaglandlin I2(PGI2), thromboxane (TXA2) and angiotensin (ANGII) in pregnant rats, and to investigate the role of these factors in the pathogenesis of pregnancy-induced hypertension(PIH).. Pregnant rats were divided into two groups randomly. Saline solution or L-nitro arginine methyl ester (L-NAME) 125 mg/day was given subcutaneously from day 14 of gestation till delivery. Systolic blood pressure, urine protein, platelet count, and weight of pups and placentae were determined. Plasma NO, ET, PGI2, TXA2 and ANGII were measured by RIA.. Pregnant rats which were given L-NAME produced physical signs similar to those of PIH, such as increase in systolic blood pressure (140.6 +/- 3.8) mmHg and urine protein (801.38 +/- 57.12) mg/L, and decrease in platelet count (533 +/- 42) x 10(9)/L and weight of pups and placentae. Compared with controls, plasma NO, PGI2 and ANG II were decreased significantly while plasma ET and TXA2 were increased significantly in rats given L-NAME.. Inhibition of NO synthesis can cause imbalance of several vaso-regulatory factors, which may be responsible for the pathogenesis of PIH.

Topics: 6-Ketoprostaglandin F1 alpha; Angiotensin II; Animals; Endothelin-1; Female; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase; Pre-Eclampsia; Pregnancy; Random Allocation; Rats; Rats, Wistar; Vasodilation

Women with prior preeclampsia are characterized by hyperinsulinemia and a 2- to 3-fold excess risk of hypertension and ischemic heart disease in later life. We therefore studied whether these women present changes in pituitary, ovarian, and endothelial factors that could also affect the risk of vascular disorders. Twenty-two women with prior preeclampsia and 22 control women matched by age and body mass index were studied an average of 17 yr after delivery. Women with prior preeclampsia had elevated serum free testosterone levels (20.6 +/- 2.2 vs. 15.0 +/- 1.3 pmol/L, mean +/- SE, P = 0.03), an elevated free androgen index (3.2 +/- 0.5 vs. 1.9 +/- 0.2, P = 0.04), and an elevated free testosterone estradiol ratio (0.089 +/- 0.017 vs. 0.046 +/- 0.006, P = 0.02). The levels of insulin-like growth factor binding protein-1 decreased as expected during a 3-h oral glucose tolerance test without differences between the groups. Levels of FSH, LH, androstenedione, dehydroepiandrosterone sulfate, and endothelin-1, as well as urinary output of prostacyclin and thromboxane A2 metabolites, showed no difference between study groups. A history of preeclampsia an average of 17 yr earlier thus appears to be associated with elevated levels of testosterone, which may contribute to the increased risk of vascular morbidity in such women.

Topics: Adult; Endothelin-1; Estradiol; Female; Glucose Tolerance Test; Humans; Hypertension; Insulin; Insulin-Like Growth Factor Binding Protein 1; Myocardial Ischemia; Pre-Eclampsia; Pregnancy; Risk Factors; Testosterone

We examined concentrations of endothelin-1 in fetal and maternal plasma samples during hypertensive and normotensive pregnancies. There were significant differences between endothelin-1 levels of eclamptic-preeclamptic mothers' newborns and healthy preterm infants (P < 0.001), but there was no significant difference between endothelin-1 levels of healthy term and preterm infants (P > 0.05).

Topics: Case-Control Studies; Eclampsia; Endothelin-1; Female; Fetal Blood; Humans; Infant, Newborn; Maternal-Fetal Exchange; Pre-Eclampsia; Pregnancy

Several observations suggest that endothelial cell dysfunction is a central pathophysiologic event of preeclampsia. Endothelin-1 (ET-1) is a vasoconstrictor peptide of the endotheliocyte and is increased in the sera of preeclamptic patients. The aim of this study was to investigate the possible regulatory mechanisms between ET-1 and nitric oxide (NO) production in cultured placental endotheliocytes. We report that endothelial cells of arterial placental blood vessels show a dysfunctional mechanism of negative feedback regulation of ET-1 production by cGMP or insufficient NO release in response to a stimulus in the form of an increasing ET-1 concentration.

Topics: Cells, Cultured; Culture Media; Cyclic GMP; Endothelin-1; Endothelium, Vascular; Feedback; Female; Humans; Nitric Oxide; Placenta; Pre-Eclampsia; Pregnancy

Hypertensive pregnant rats with inhibition of NO synthase are frequently considered as model of pre-eclampsia with proteinuria, hypertension and elevated endothelin (ET-1) blood levels. We describe here the cardiovascular in vivo effects of ET-1 in this rat model since ET-1 and NO are both important vasoactive mediators in uteroplacental circulation. From day 13 of gestation 2 groups of Wistar female rats were fed control (C) or nitroarginine enriched diet (0.063%, Treated: T). On gestational day 20 mean arterial pressure (MAP, mmHg) was measured via a carotid catheter in pentobarbital (60 mg/kg) anesthetized rats. After chronic NO synthase inhibition hypertension develops; MAP on day 20: 158 +/- 2.2 in T and 113 +/- 2.2 in C, p < 0.001. ET-1 bolus injection (0.1 nmol/kg) is rapidly followed by a decrease in blood pressure significantly more important in T: -46 +/- 5.1 than in C: -30 +/- 2.2. In vivo depressor effect is blocked by the specific antagonist BQ-788. After inhibition of cycloxygenase with acetylsalicylic acid (27 mumol/kg, 30 min before) the hypotension is not modified. Since NO and PGI2 productions are not expected in our conditions, vasodepressor effect can be explained by an endothelial hyperpolarazing factor (EDHF). In conclusion in vivo ET-1 hypotensive effects in pregnant rats are mediated by ETB receptors and more pronounced in hypertensive NO-deprived animals.

Topics: Animals; Disease Models, Animal; Endothelin Receptor Antagonists; Endothelin-1; Female; Hypotension; Nitric Oxide Synthase; Oligopeptides; Piperidines; Pre-Eclampsia; Pregnancy; Pregnancy, Animal; Rats; Rats, Wistar

To examine the effect of endothelin-1 (ET-1) on spontaneous contractile activity and the effects of nimodipine and isradipine on ET-1-induced contractile responses in myometrial strips isolated from normal pregnant and preeclamptic women.. . Isolated myometrial strips were obtained from seven normal pregnant and seven preeclamptic women undergoing elective cesarean section and the strips were mounted in organ baths for recording of isometric tension. The effect of increasing concentration of ET-1 on spontaneous contractions and effects of increasing concentration of nimodipine and isradipine on ET-1-induced contractions were recorded.. ET-1 dose-dependently (10(-11)-10(-8) M) increased the amplitude and frequency of spontaneous contractions in all myometrial strips obtained from normal pregnant and preeclamptic women. The increase in the amplitude of contractions in preeclamptic strips was significantly higher than that of normal strips. The increase in amplitude of contractions in normal and preeclamptic strips reached statistical significance beginning from the concentrations of 10(-9) M and 10(-11) M, respectively. ET-1 (10(-8) M) also increased the basal tone of all myometrial strips isolated from normal pregnant and preeclamptic women. When ET-1 (10(-8) M)-contracted myoinetrial strips were exposed to increasing concentrations of nimodipine (10(-6)-3x10(-5)M) and isradipine (10(-5)-3x10(-4) M), nimodipine and isradipine dose-dependently decreased the amplitude and frequency of contractions.. The increase in contractile response with ET-1 was significantly higher in myometrial strips isolated from preeclamptic women compared to those of myometrial strips isolated from normal pregnant women. These increases in contractile response are at least in part mediated by dihydropyridine-sensitive calcium channels, since they were significantly reduced in the presence of increasing concentrations of nimodipine and isradipine.

Topics: Calcium Channel Blockers; Dose-Response Relationship, Drug; Endothelin-1; Female; Humans; In Vitro Techniques; Isradipine; Myometrium; Nimodipine; Pre-Eclampsia; Pregnancy; Uterine Contraction

To investigate the relationship of nitric oxide (NO), endothelin-1 (ET-1) levels and pregnancy induced hypertension (PIH).. 60 patients with PIH, 45 normal pregnant women and 15 normal non-pregnant women were studied. Plasma NO levels were determined. The stable metabolic product NO2-/NO3- of NO was letermined by Griess reaction. Plasms ET-1 levels were measured with radioimmunoassay.. The NO2-/NO3- levels of the normal pregnancy group were significantly higher than those of the control group (P < 0.01), particularly in the second trimester of pregnancy. The NO2-/NO3- level of PIH was significantly lower in maternal plasma than that of the last trimester of normal pregnancy (P < 0.01) and nonpregnancy (P < 0.05), and it decreased with the disease development. In severe PIH the umbilical venous blood NO2-/NO3- level was significantly lower than that in the normal term pregnancy group (P < 0.01). The maternal plasma ET-1 level in PIH was significantly higher than that in the normal term pregnancy and control groups (P < 0.01).. PIH might be related to decreasing synthesis and release of NO, and increasing ET-1 production.

Topics: Adult; Endothelin-1; Female; Humans; Nitric Oxide; Pre-Eclampsia; Pregnancy

We examined the endothelin (ET)-1 and -2 concentration in peripheral blood serum of 27 pregnant patients with EPH gestosis who underwent cesarean section between the 32nd and 38th week of gestation (group Gc). The control group consisted of 26 healthy pregnant women who underwent cesarean section due to fetal malpositions (group Kc). ET concentration in umbilical venous blood serum in 22 cases of EPH gestosis (group Gp) and 20 cases from the control group (Kp) was measured after delivery. ET concentration was determined with use of a radioimmunoassay method after extraction with column chromatography. The mean ET concentration was 41.55 pg/ml in group Gc and was significantly higher than in group Kc-6.77 pg/ml. The mean ET concentration in umbilical blood serum in group Gp was 50.59 pg/ml and was significantly higher than in Gc and Kp groups-where ET concentration was 17.11 pg/ml. These studies indicate that the high level of ET may play an important role in pathogenesis of EPH gestosis as well as having influence on uteroplacental and umbilicoplacental circulation.

Topics: Endothelin-1; Endothelin-2; Female; Fetal Blood; Humans; Pre-Eclampsia; Pregnancy; Pregnancy Complications, Cardiovascular; Reference Values

We hypothesized that aspirin Mg++, and dihydralazine affect the release of vasoactive agents from cultured human placental trophoblast.. Cytotrophoblasts isolated from placentas of preterm or term deliveries of 14 healthy control women and 15 preeclamptic women were cultured in Dulbecco's modified Eagle's medium for 5 days in the presence or absence of either 0.1 mmol/L aspirin, 3 mmol/L magnesium chloride, or 136 ng/ ml dihydralazine. Vasoactive substances were quantitated by radioimmunoassay with mean +/- SEM percentage of untreated cells (= 100%) compared by the Mann-Whitney U test and analysis of variance.. Aspirin inhibited (p < 0.01) both thromboxane and prostacyclin on days 1 and 2 in culture but not on days 3 to 5 unless the Dulbecco's modified Eagle's medium was supplemented with arachidonic acid. Aspirin inhibition was greater (p < 0.01) for thromboxane in cells cultured 24 hours after preeclamptic pregnancy (preterm 29.9% +/- 6.8%, term 20.1% +/- 5.9%) compared with normal controls (preterm 66.3% +/- 10.6%, term 68.9% +/- 11.6%). Aspirin reduced (p < 0.01) the ratio of thromboxane to prostacyclin in media of cells from preeclampsia (untreated 27.8 +/- 7.2, aspirin 13.3 +/- 4.4), but aspirin had no effect on this ratio in cultures from control normal pregnancies (untreated 6.8 +/- 2.9, aspirin 4.8 +/- 1.1). Neither magnesium chloride nor dihydralazine affected trophoblast prostanoid production, and no drug altered the media levels of angiotensin II, endothelin-1, or leukotriene B4.. Aspirin selectively inhibits trophoblast prostanoid production. This inhibition depends on the availability of arachidonic acid and the presence or absence of preeclampsia. Magnesium and dihydralazine effects in pregnancy are not related to altered release of trophoblast vasoactive compounds.

Topics: Angiotensin II; Antihypertensive Agents; Aspirin; Cells, Cultured; Cyclooxygenase Inhibitors; Dihydralazine; Endothelin-1; Epoprostenol; Female; Humans; Leukotriene B4; Magnesium Chloride; Pre-Eclampsia; Pregnancy; Thromboxane B2; Trophoblasts

Whether the serum levels of endothelin, a vasoconstrictive peptide produced in the endothelial cell, increase in preeclamptic patients is still controversial. We performed immunohistochemical studies to observe the changes in endothelin-1 (ET-1) in preeclamptic kidney tissues. The monoclonal anti-human ET-1 antibody (Yamasa, Japan) and anti-von Willebrand factor (vWF, Dako, Denmark), a marker of endothelial cells, were used for the studies by the strepto-avidin-biotin peroxidase method (ABC-POD Kit, Wako, Japan). Twenty-nine patients and 12 normal controls were divided into four groups. The preeclamptic group included 14 patients diagnosed with preeclampsia by clinical symptoms of hypertension, proteinuria, and edema occurring in late pregnancy and as having preeclamptic nephropathy. They underwent renal biopsy 16.7 +/- 1.0 (mean +/- SEM) days after delivery. The nephrotic group comprised 10 normotensive nonpregnant patients with nephrotic-range proteinuria examined through biopsy before treatment (six cases of minimal change, two of focal segmental glomerulosclerosis, one of membranous nephropathy, and one of IgA nephropathy). The pregnant women with preexisting glomerular disease group included five pregnant women with normal renal function who were normotensive and had no increase in the amount of proteinuria throughout pregnancy. They underwent renal biopsy 10.8 +/- 2.9 days after delivery (two cases of membranous nephropathy, one of focal segmental glomerulosclerosis, one of thin basement membrane disease, and one of non-IgA mesangioproliferative glomerulonephritis). The normal kidney group comprised 12 healthy tissue samples taken from nephrectomized kidneys (five cases of renal cell carcinoma, one case of lipofibrosarcoma, and six cases of kidney transplant donors). In these four groups, ET-1 and vWF showed equally positive staining in small arteries. VWF also showed positive staining in arterioles and peritubular capillaries in all groups. Although the glomeruli showed positive staining with ET-1 along the capillary walls in the normal group and the nonpregnant nephrotic group, they showed very weak or negative results in the preeclamptic group. Moreover, gravida with underlying glomerular disease without superimposed preeclampsia also showed negative findings of ET-1 in the glomeruli. The glomeruli in the four groups showed positive findings, with vWF readings the same as in the controls. These results indicate that the production of ET-1 in the

Topics: Adult; Analysis of Variance; Biopsy; Endothelin-1; Female; Glomerulonephritis; Humans; Immunoenzyme Techniques; Immunohistochemistry; Kidney; Middle Aged; Nephrotic Syndrome; Pre-Eclampsia; Pregnancy

To examine endothelin-1 (ET-1) concentrations longitudinally throughout pregnancy in healthy and insulin-dependent diabetic women and to evaluate the relationship between ET-1 and big ET-1 in normal pregnancy.. Venous blood samples were obtained consecutively in gestational weeks 18, 28, and 38 from 40 healthy women with uneventful pregnancies and 24 pregnant women with IDDM. By radioimmunoassay, plasma ET-1 and big ET-1 were analyzed in the healthy women and plasma ET-1 in the diabetic women.. In the diabetic pregnant women, plasma ET-1 levels were significantly higher than in healthy pregnant women during the entire observation period (P < 0.001), but did not change with advancing gestational age. Five of the diabetic, but none of the healthy pregnant women, developed preeclampsia. ET-1 levels did not differ between the diabetic women who developed preeclampsia and those who did not. Plasma ET-1 levels in healthy pregnant women were within the range of those in healthy nonpregnant women and did not change during pregnancy. The big ET-1 levels increased and the ET-1/big ET-1 ratio decreased significantly during the observation period.. Plasma ET-1 levels do not change with advancing gestational length. During normal pregnancy, the ET-1/big ET-1 ratio decrease, indicating a suppressed converting enzyme activity or altered clearance of ET-1. Pregnant women with IDDM have markedly elevated ET-1 levels. Although diabetic women with and without preeclampsia did not differ with respect to endothelial dysfunction, as reflected by elevated ET-1 concentration, we cannot exclude that altered endothelial function may be of importance for the increased frequency of preeclampsia in pregnant IDDM patients.

Topics: Adult; Analysis of Variance; Diabetic Angiopathies; Endothelin-1; Endothelins; Female; Gestational Age; Humans; Pre-Eclampsia; Pregnancy; Pregnancy in Diabetics; Pregnancy Trimester, Second; Pregnancy Trimester, Third; Protein Precursors; Radioimmunoassay; Reference Values

To determine the site of origin of increased concentrations of plasma endothelin-1 in patients with severe preeclampsia.. Twelve patients with severe preeclampsia undergoing an indicated abdominal delivery had endothelin-1 levels measured from plasma specimens drawn from right and left uterine and antecubital veins before delivery and after placenta removal with uterine curettage. Twelve uncomplicated control patients undergoing abdominal delivery had endothelin-1 concentrations drawn by an identical protocol. Clinical staff members were blinded to endothelin-1 results and laboratory staff were blinded to patient group assignment and sample source. Endothelin-1 plasma concentrations were determined by radioimmunoassay and data were analyzed by paired t test.. No difference in endothelin-1 concentration was noted with respect to placental location, central versus peripheral, or predelivery versus postdelivery sampling procedures. Overall, patients with preeclampsia had higher plasma concentrations of endothelin-1 (mean 11.0 +/- 6.6 pg/mL) compared with normotensive patients (mean 8.4 +/- 6.7 pg/mL, P < .005).. The decidual-placental interface does not appear to be the source of increased plasma endothelin-1 concentrations found in severe preeclampsia. The origin of this increase remains uncertain.

Topics: Adult; Blood Specimen Collection; Case-Control Studies; Delivery, Obstetric; Endothelin-1; Female; Humans; Placenta; Pre-Eclampsia; Pregnancy; Severity of Illness Index; Single-Blind Method; Time Factors

A defect in placental function has been suggested to be associated both with preeclampsia (PE), with or without concomitant intrauterine growth retardation (IUGR), and with IUGR as a single entity. Our aim was to compare the mRNA expression of the growth-related protooncogenes c-fos and c-jun and the vasoconstrictor and growth factor endothelin-1 (ET-1) in placentas from normal pregnancies with those of PE and IUGR. The mRNA expression of c-jun was significantly higher in all groups of complicated pregnancies while ET-1 and c-fos mRNA expression was significantly higher only in the group with IUGR. These results support the concept that an aberrant placental mRNA expression of the ET-1, c-fos and c-jun genes is part of an altered pattern of gene expression in pathological pregnancies.

Topics: Biopsy; Cohort Studies; Endothelin-1; Female; Fetal Growth Retardation; Gene Expression Regulation, Developmental; Genes, fos; Genes, jun; Humans; Placenta; Pre-Eclampsia; Pregnancy; RNA, Messenger

In order to investigate the pathophysiological significance of anti-endothelial cell antibody (AECA) in pre-eclampsia, the effects of AECA on endothelin-1 (ET-1) and prostaglandin I2 (PGI2) release from cultured human umbilical vein endothelial cells (HUVEC) was evaluated. Serum samples were taken from 85 pre-eclamptic and 20 normal pregnant women. Anti-endothelial cell antibody was measured by ELISA using HUVEC. The release of ET-1 and 6-keto PGF1-alpha, a stable metabolite of PGI2, from HUVEC were evaluated after incubation with IgG-AECA-positive sera and IgG isolated from AECA-positive sera. The incidence of IgG- and IgM-AECA was 24.7 and 8.2%, respectively. The release of ET-1, in the medium containing IgG-AECA-positive sera was significantly greater than in the medium containing IgG-AECA-negative sera. There was significant correlation between the levels of IgG-AECA and the release of ET-1 from endothelial cells. The ET-1 release by IgG isolated from AECA-positive sera was greater than that from AECA-negative sera. However, the release of 6-keto PGF1-alpha by AECA-positive sera was not significantly different from that of AECA-negative sera. It is concluded that IgG-AECA in pre-eclampsia increases ET-1 release from endothelial cells and that AECA may affect local vascular function in this disorder.

Topics: 6-Ketoprostaglandin F1 alpha; Autoantibodies; Cells, Cultured; Dose-Response Relationship, Immunologic; Endothelin-1; Endothelium, Vascular; Female; Humans; Immunoglobulin G; Interleukin-1; Pre-Eclampsia; Pregnancy; Time Factors; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

Plasma concentration of endothelin-1, a potent vasoconstrictor produced by the vascular endothelium, has been observed to be significantly increased in a number of pathophysiological states, including preeclampsia. In the present study we have evaluated the effects of elevated plasma endothelin-1 in pregnant sheep by continuous exogenous endothelin-1 administration. Nine pregnant ewes (110+/-5 days' gestation) were instrumented for measurements of maternal mean arterial pressure, renal blood flow, and uterine blood flow. After recovery, endothelin-1 was infused intravenously for 4 hours at a dose that was adjusted to raise mean arterial pressure by approximately 20 mm Hg by the end of the first hour (range 5 to 20 ng/kg per minute). Mean arterial pressure, renal blood flow, uterine blood flow, urinary protein excretion, hematocrit, and plasma endothelin-1 concentration were measured hourly, and renal and uterine vascular resistances were calculated. Endothelin-1 produced significant increases (% change from baseline at t=4 hours) in mean arterial pressure (45+/-8%), renal vascular resistance (353+/-66 %), and uterine vascular resistance (59+/-21%). Endothelin-1 also increased microvascular permeability both systemically and within the kidney, as suggested by marked increases in hematocrit (0.27+/-0.01 to 0.32+/-0.01) and urinary protein concentration (0.95+/-0.1 to 7.9+/-3.2 mg/mL per mg creatinine). There was a highly significant correlation (P<.0001) between plasma endothelin-1 and mean arterial pressure, renal vascular resistance, uterine vascular resistance, hematocrit, and urinary protein content in all sheep studied. In addition, plasma endothelin-1 corresponded well with the time course of the changes in cardiovascular parameters and urinary protein excretion observed. These results provide evidence to suggest that elevation of circulating endothelin-1 in pregnant sheep can produce cardiovascular and hemodynamic changes that in many ways resemble the human disease preeclampsia. This supports the hypothesis that endothelial cell damage and/or dysfunction that is associated with increased production of endothelin-1 could directly contribute to the progression of preeclampsia.

Topics: Animals; Blood Pressure; Endothelin-1; Female; Hematocrit; Hemodynamics; Humans; Infusions, Intravenous; Pre-Eclampsia; Pregnancy; Pregnancy, Animal; Proteinuria; Regional Blood Flow; Renal Circulation; Sheep; Time Factors; Uterus; Vascular Resistance

This study was conducted (1) to determine in vitro placental villous cytotrophoblast secretion of prostacyclin, prostaglandin E2, and endothelin-1, (2) to examine the effect of serum from normal and preeclamptic women on secretion of these vasoactive substances, and (3) to determine whether responses to these sera by cytotrophoblasts from preeclamptic pregnancies are different from those of normal pregnancies.. Cytotrophoblasts isolated from human placentas collected at cesarean section from normal and preeclamptic women were incubated for 20 hours in 20% (vol/vol) sera from preeclamptic or gestational age-matched normal pregnant women. Levels of prostacyclin (measured as 6-keto-prostaglandin F1alpha), prostaglandin E2, and endothelin-1 were measured in cytotrophoblast supernatants.. In normal pregnancy sera preeclamptic cytotrophoblasts secreted significantly lower amounts of prostacyclin and prostaglandin E2 but higher amounts of endothelin-1 than did normal cytotrophoblasts. In preeclamptic sera the abnormality of prostacyclin secretion by preeclamptic cytotrophoblasts was partially corrected, but there was no effect on prostaglandin E2 or endothelin-1 secretion. Preeclamptic sera had no effect on secretion by normal cytotrophoblasts.. The differences between normal and preeclamptic cytotrophoblasts in prostacyclin, PGE2, and endothelin-1 secretion and in response to preeclamptic serum suggest altered arachidonic acid metabolism in preeclampsia.

Topics: Blood Physiological Phenomena; Cells, Cultured; Chorionic Villi; Dinoprostone; Endothelin-1; Epoprostenol; Female; Humans; Pre-Eclampsia; Pregnancy; Trophoblasts

Topics: Adult; Biomarkers; Endothelin-1; Female; Humans; Linear Models; Pre-Eclampsia; Predictive Value of Tests; Pregnancy; Prospective Studies; Reproducibility of Results; Sensitivity and Specificity

Endothelial cells isolated from umbilical veins (HUVEC) and from decidual biopsies collected at caesarean section delivery (DEC) from both normal (N DEC) and pre-eclamptic (PE DEC) women, were maintained in culture until passage 2, when the effect on growth of removing heparin/ECGS (endothelial cell growth supplement) from the culture medium was assessed, and the effects of heparin-free incubation and of the Ca2+ ionophore A23187 on endothelin-1, prostacyclin and prostaglandin E2 secretion over a 24 h period were examined. Cell growth slowed significantly in all three cell types in the absence of heparin/ECGS, and cell death occurred in 1/3 samples of HUVEC, 4/6 of N DEC, but 0/2 of PE DEC over 4 days. During the 24 h incubation for prostaglandin in medium without these growth factors, there was further cell death in N DEC. The addition of A23187 to this stress led to a reduction in cell number in both N DEC and HUVEC, and to a lesser extent in PE DEC. Prostaglandin and endothelin-1 levels were higher in the absence of heparin/ECGS in all cell types There was significant suppression of endothelin-1 secretion at 24 h incubation, and stimulation of prostaglandin secretion by A23187. Incubation without heparin/ECGS magnified the effect of A23187 on prostaglandin secretion, although the proportional change was similar if compared to controls without heparin/ECGS. Withdrawal of heparin/ECGS from the medium altered the balance of PGE2/PGI2 secretion by HUVEC, but not DEC. Endothelial cells require the presence of heparin/ECGS for optimum growth and viability, and N DEC are particularly dependent on these growth factors. PE DEC appear relatively 'hardy' in this regard. The addition of a further potentially toxic stimulus may result in cell death, and experiments to be conducted in limited medium must take this into account. There are both qualitative and quantitative differences in the effects of these stimuli on secretion of vasoactive substances, between decidual and umbilical vein endothelial cells.

Topics: Calcimycin; Calcium; Cell Death; Cell Division; Cells, Cultured; Culture Media; Decidua; Endothelin-1; Endothelium, Vascular; Female; Growth Substances; Heparin; Humans; Pre-Eclampsia; Pregnancy; Prostaglandins; Umbilical Veins

Endothelin-1 (ET-1) is a potent vasoconstrictor released by vascular endothelium. Because endothelial cell damage is considered determinant in the pathophysiology of pregnancy-induced hypertension (PIH), this study was conducted to evaluate the role of ET-1 produced by feto-placental tissues in PIH. Amniotic fluid samples obtained by amniocentesis from patients with PIH (N = 33), intrauterine growth retardation (IUGR) (N = 16), and PIH associated with IUGR (N = 12) were evaluated for ET-1 and compared to 42 normotensive pregnancies using a specific radioimmunoassay. ET-1 levels were significantly increased in PIH (35.6 +/- 1.9 pg/ml) and IUGR groups (33.8 +/- 4.6 pg/ml) compared to controls (20.8 +/- 1.4 pg/ml) (P < 0.01). In patients with PIH associated with IUGR, ET-1 concentrations were higher (P < 0.05) with no correlation with the severity of IUGR. Our data indicate that in PIH and IUGR ET-1 production and/or secretion is enhanced in the amniotic compartment, suggesting that the peptide may contribute to the pathophysiologic modification observed in these conditions.

Topics: Adult; Amniotic Fluid; Endothelin-1; Extraembryonic Membranes; Female; Fetal Growth Retardation; Fetus; Gestational Age; Humans; Organ Size; Placenta; Pre-Eclampsia; Pregnancy

To study the concentrations of endothelin-1 (ET-1) and its precursor, big ET-1, in samples of amniotic fluid, fetal urine, umbilical arterial and venous blood, retroplacental blood and maternal uterine and brachial venous blood obtained from normal and preeclamptic women. Samples were collected from 31 healthy pregnant women (16 in labor and 15 undergoing elective cesarean section) and 35 preeclamptic women (9 in labor and 26 undergoing cesarean section). Big ET-1 and ET-1 were measured by radioimmunoassay and the ET-1 to big ET-1 ratios were calculated. In preeclamptic women there was a significant elevation of ET-1 in the maternal brachial and uterine veins and of big-ET-1 in the brachial vein. The ET-1 concentrations and the ET-1/big ET ratios were significantly higher on the fetal side (i.e., in the umbilical vein and amniotic fluid) than in maternal blood, but in these sampling locations there was no difference between the normal pregnancy and preeclampsia group. A significant negative correlation (r = -0.67, P < 0.01) was found between plasma ET-1 in the umbilical vein and birth weight in the preeclamptic group. ET-1 was significantly higher in amniotic fluid than in the first neonatal urine of corresponding pregnancies (15.0 +/- 2.0 vs. 3.0 +/- 2.9 pmol/l, P < 0.05). The ET-1 and big ET-1 concentrations are significantly higher in fetal plasma and amniotic fluid than in maternal plasma, indicating increased endothelin converting enzyme activity and increased ET-1 production in utero. The elevated ET-1 concentration in maternal blood in preeclamptic compared with normal pregnant women and the negative correlation between ET-1 in the umbilical vein and birth weight suggest that ET-1 plays a pathophysiological role in preeclampsia and other conditions with intrauterine growth restriction.

Topics: Adult; Amniotic Fluid; Birth Weight; Endothelin-1; Endothelins; Female; Fetal Blood; Humans; Pre-Eclampsia; Pregnancy; Protein Precursors; Statistics as Topic

To investigate the possible role of endothelin-1 (ET-1) and atrial natriuretic peptide (ANP) in the pathogenesis of pregnancy-induced hypertension (PIH).. A total of 110 normal pregnant women (in three trimesters, labour or postpartum) and 30 patients with PIH were studied by measuring plasma ET-1 and ANP levels by radioimmunoassay; 23 normal non-pregnant women were selected as controls.. Compared with normal non-pregnant women, plasma ET-1 levels were significantly decreased in normal pregnant women during all three trimesters. Plasma ET-1 level was significantly increased in the 2nd stage of labour, compared with that in the 3rd trimester. There were significant positive correlation between plasma ET-1 level and mean arterial pressure in normal non-pregnant women and normal pregnant women in all three trimesters. Compared with matched normal pregnant women, plasma ET-1 and ANP levels were significantly increased, while plasma ANP/ET-1 ratio was significantly decreased in PIH patients. Significant positive correlations existed between plasma ET-1 level and mean arterial pressure or the score index of the severity of PIH. After the treatment with magnesium sulfate infusion, plasma ET-1 and ANP levels were significantly decreased, but plasma ANP/ET-1 ratio was significantly increased in PIH patients.. Augmentation of ET-1 secretion and attenuation of ANP function may be responsible for the development of PIH. ET-1 secretion may be indirectly influenced by magnesium in PIH.

Topics: Adult; Atrial Natriuretic Factor; Endothelin-1; Female; Humans; Pre-Eclampsia; Pregnancy; Radioimmunoassay; Vasoconstriction

To examine a possible role for endothelin-1 (ET-1) and conversion of big ET-1 to ET-1 in the pathophysiology of pre-eclampsia, we measured plasma levels of ET-1 and big ET-1 in 16 women with pre-eclampsia in the third trimester and compared them with those in 11 age-matched normotensive pregnant women and in 10 age-matched pregnant women with chronic hypertension in the third trimester. The plasma concentrations of ET-1 and big ET-1 in the normotensive pregnant women were significantly lower than those in 16 non-pregnant women with a higher molar ratio of big ET-1 to ET-1 in the former group. The plasma concentrations of ET-1 and big ET-1 in the women with pre-eclampsia, on the other hand, were significantly higher than those in the normotensive pregnant women and the molar ratio of big ET-1 to ET-1 in the former group was less than that in the latter group. In sharp contrast, plasma ET-1 and big ET-1 levels in the pregnant women with chronic hypertension were not significantly different from those in the normotensive pregnant women. When examined after delivery, elevated plasma ET-1 and big ET-1 in the women with pre-eclampsia declined, with restoration of normal blood pressure, to the levels in the normotensive women after parturition. There were no significant differences of the levels of ET-1 and big ET-1 in umbilical venous plasma and simultaneously drawn maternal plasma at cesarean section between normotensive pregnant women and women with pre-eclampsia, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Endothelin-1; Endothelins; Female; Humans; Hypertension; Postpartum Period; Pre-Eclampsia; Pregnancy; Protein Precursors; Umbilical Veins