endothelin-1 and Hypertension--Pregnancy-Induced

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

Hypertension occurs in 6 to 10 percent of pregnancies. It remains one of the most common disorders in pregnancy and the leading causes of maternal and fetal morbidity The changes in blood vessel endothelium have impact on the pathogenesis of hypertension and preeclampsia.. The aim of this study was to establish endothelin- 1 and lipids peroxides content in blood during hypertension and the influence of vitamin C and E supplementation on the concentration of both parameters.. Two study groups (pregnancy complicated with hypertension, pregnancy complicated with hypertension treated with vitamins C and E) and a control group with uncomplicated pregnancies were distinguished. Blood samples from maternal peripheral venous circulation were collected and ET-1 and lipids peroxides levels were determined from the blood samples.. Concentration of endothelin-1 in the group with hypertension and with vitamin supplementation was INCREASED (66.18 +/- 26.66 pg/ml) in comparison with normal pregnant (36.50 +/- 13.25) and hypertension group (41.02 +/- 15.98). The difference was significant. Lipid peroxides concentrations were significantly higher in the group with hypertension (1.18 +/- 0.69) in comparison with both groups - controls (0.73 +/- 0.35) and the group with hypertension and vitamin supplementation (0.77 +/- 0.42).. No significant differences in the endothelin- 1 level between healthy pregnant and pregnant women with hypertension were found. Vitamin supplementation decreases the concentrations of lipid peroxides.

Topics: Administration, Oral; Ascorbic Acid; Biomarkers; Drug Administration Schedule; Endothelin-1; Female; Humans; Hypertension; Hypertension, Pregnancy-Induced; Lipid Peroxides; Pregnancy; Vitamin E

Hypertensive disorders complicating pregnancy (HDCP) is a systemic disease among pregnant women. Therefore, the prevention and prediction of hypertension during pregnancy are critical. This study aimed to clarify whether the vascular endothelial function of women with gestational hypertension was linked to placental growth factor. A total of 200 pregnant women were enrolled in our study and subsequently divided into two groups: the HDCP group and the normal pregnancy controls. The levels of serum placental growth factor, as well as plasma endothelin-1 and nitric oxide, between the two groups were measured. In addition, the endothelial function indexes, including pressure-strain elasticity coefficient (EP), the common carotid stiffness index (β), arterial compliance, single-point pulsed-wave velocity, and augment index (AI) of bilateral common carotid arteries, were compared between the HDCP and control groups using the echo tracking technique. In our study, the level of placental growth factor in the HDCP group was significantly lower than the control group. Furthermore, our results clarified that endothelin-1 increased while nitric oxide decreased in the HDCP group compared with the control group. On the other hand, we found that EP, β, pulsed-wave velocity and augment index values were significantly higher in the HDCP group than in the control group (P < 0.001). However, the value of arterial compliance was significantly decreased in patients of the HDCP group compared with the control group (P < 0.001). In conclusion, the association between serum placental growth factor and vascular endothelial function in HDCP could serve as a more accurate predictive factor of pregnant hypertension.

Topics: Case-Control Studies; Endothelin-1; Female; Humans; Hypertension, Pregnancy-Induced; Nitric Oxide; Placenta Growth Factor; Pregnancy

Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) has been identified previously in the pathogenesis of hypertension and some gestational diseases. However, the biological functions of MALAT1 in pregnancy-induced hypertension (PIH) are still poorly understood. Herein, we aim to explore the functional relevance of MALAT1 in PIH and to explain the potential underlying mechanisms. We found that the levels of ET-1 and MALAT1 were upregulated and that of miR-150-5p were downregulated in the serum of pregnant women with PIH and the aortic endothelial cells (ECs) of reduced uterine perfusion pressure (RUPP)-induced rat models. In aortic ECs, MALAT1 could competitively bind to miR-150-5p to upregulate the expression of ET-1. The MALAT1/miR-150-5p/ET-1 axis regulated the expression of endothelin B receptor (ETBR) in aortic ECs leading to oxidative stress imbalance and increased the release of proinflammatory cytokines (IL-18 and IL-1β), which concurrently activated the NF-κB pathway to regulate the ETBR expression and to stimulate smooth muscle cell (SMC) contraction. Furthermore, silencing MALAT1 could alleviate the hypertensive symptoms of RUPP-induced rat models. Taken conjointly, the upregulation of MALAT1 can reduce the expression of ET-1 by competitively binding to miR-150-5p, which enhances the expression of ETBR via the activation of the NF-κB pathway in SMCs, thus exacerbating the hypertensive symptoms in the RUPP-induced rat models.

Topics: Adult; Animals; Apoptosis; Cell Proliferation; Endothelin-1; Female; Gene Expression Regulation; Humans; Hypertension, Pregnancy-Induced; Inflammation; Interleukin-1beta; Male; MicroRNAs; NF-kappa B; Oxidative Stress; Pregnancy; Rats; Rats, Wistar; RNA, Long Noncoding; Signal Transduction; Young Adult

Quercetin was reported to be crucial for a broad range of activities, including attenuating inflammation, platelet aggregation, capillary permeability, and lipid peroxidation. However, the effect of quercetin in hypertension during pregnancy, was not fully understood.. The model of hypertension in pregnancy was established in rats by reduced uterine perfusion pressure (RUPP). Quercetin was administrated by gavage. Systolic blood pressure (SBP) and diastolic blood pressure (DBP) were measured using the CODA 6 BP system. Plasma concentrations of Endothelin-1 (ET-1), soluble fms-like tyrosine kinase-1 (sFlt-1), and vascular endothelial growth factor (VEGF) were detected using enzyme-linked immunosorbent assay kits. The mRNA and protein levels of ET-1 and endothelin-1 type A receptor (ET. In RUPP induced rats, quercetin treatment decreased SBP and DBP, fetal resorptions percentage, plasma ET-1 and sFlt-1 concentrations, ET-1 and ET. Quercetin attenuates RUPP induced hypertension in pregnant rats through the regulation of ET-1 and ET

Topics: Animals; Antihypertensive Agents; Blood Pressure; Disease Models, Animal; Endothelin Receptor Antagonists; Endothelin-1; Female; Fetal Weight; Hypertension, Pregnancy-Induced; Male; Peptides, Cyclic; Perfusion; Placenta; Pregnancy; Quercetin; Rats, Sprague-Dawley; Receptor, Endothelin A; Uterus; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-1

Recently, advanced maternal age (AMA) has been increasing due to late marriage and assisted reproductive technology. AMA is high-risk pregnancy associated with the life-threatening diseases such as hypertensive disorders of pregnancy (HDP). Recently we have reported novel AMA model mice using aged spontaneous pregnant mice, and found that the phenotypes of AMA model mice reflect the same characteristics as human AMA. We have also demonstrated that atypical angiogenic factors profiles including soluble VEGF-R1 (sFlt-1) and placental growth factor in both AMA pregnant women and AMA model mice. VEGF-endothelin-1 system have been also known as one of HDP-associated factors, however, there has been few reports on the relation between VEGF-endothelin-1 system and AMA. In this study, we investigated the profiles of VEGF-endothelin-1 system using our model mice's samples. As a result, VEGF and endothelin-1 levels were not significantly different between AMA and young individuals. Our results indicated that the mechanisms of hypertension in AMA may differ from those in young individuals from the point of VEGF-endothelin-1 system.

Topics: Aging; Animals; Disease Models, Animal; Embryo, Mammalian; Endothelin-1; Female; Gene Expression Regulation; Humans; Hypertension, Pregnancy-Induced; Maternal Age; Mice; Mice, Inbred ICR; Pregnancy; Vascular Endothelial Growth Factor A

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

Studies have shown that a change in endothelin receptor expression in the artery is related to pregnancy-induced hypertension (PIH). However, the mechanism underlying this change remains unclear.. To test whether the distribution of endothelin receptor type-A (ETAR) and type-B (ETBR) plays an important role in PIH, a reduction of uterine perfusion pressure (RUPP) rat model was used to mimic some of the features of PIH; the resulting variable endothelin receptor expression was investigated in the media and intima of the aorta. Single vascular smooth muscle cells (VSMCs) were isolated from RUPP and normal pregnant (NP) rats to study the effect of ETAR and ETBR in smooth muscle cells.. Compared with NP rats, RUPP rats had a significant redistribution of ETBR expression in the intima and media, while there was no significant difference in ETAR expression between the two groups. ETBR upregulation in VSMCs enhanced cellular contraction and contributed to PIH. The TNF-α plasma levels in RUPP rats were two-fold higher than those of NP rats, which upregulated the expression of ETBR in VSMCS through the NF-κB pathways in RUPP rats.. Redistribution of ETBR between the media and intima played an important role in the pathogenesis of PIH.

Topics: Animals; Blood Pressure; Cells, Cultured; Endothelin A Receptor Antagonists; Endothelin-1; Endothelins; Female; Hypertension, Pregnancy-Induced; Interleukin-6; Interleukin-8; Myocytes, Smooth Muscle; NF-kappa B; Peptide Fragments; Peptides, Cyclic; Pregnancy; Rats; Rats, Sprague-Dawley; Receptor, Endothelin A; Receptor, Endothelin B; Transcription Factor RelA; Tumor Necrosis Factor-alpha; Tunica Intima; Uterus; Vascular Remodeling

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

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

Pregnancy induced hypertension (PIH) is major contributor to maternal death in developing countries. Endothelin-1 (ET-1) is the most potent vasoconstriction agent known and its serum levels are increased in PIH. Therefore it is important to elucidate maternal and neonatal factors which influence endothelin-1 serum levels. 100 pathological pregnancies and 88 controls were analyzed for blood endothelin-1 and their anthropometric and clinical data were collected. In maternal blood ET-1 levels were strongly predicted by diagnosis, therapy and BMI, while umbilical cord ET-1 levels were strongly predicted by gestational age, therapy and delivery termination. Positive correlation between BMI and ET-1 levels suggest that obese pregnant women have increased risk for cardiovascular diseases. Inverse relationship between Apgar and umbilical ET-1 indicates that ET-1 could be considered as a prognostic marker in cases of neonatal asphyxia.

Topics: Adult; Anthropometry; Apgar Score; Asphyxia Neonatorum; Endothelin-1; Female; Humans; Hypertension, Pregnancy-Induced; Infant, Newborn; Male; Pregnancy; Risk 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

Previous investigations suggested that agonistic autoantibodies to the angiotensin II type I receptor (AT1-AA) might mediate a hypertensive response through dysregulation of the endothelin-1 system. AT1-AA induced hypertension was attenuated by the AT1 receptor and/or endothelin-1 type A receptor antagonists.. This study was undertaken to determine if AT1-AA induced hypertension was associated with renal endothelial dysfunction.. We compared the vascular reactivity of renal interlobar arteries from normal pregnant control rats and AT1-AA long-term infused pregnant rats in the presence and absence of endothelin type A (ET(A)) receptor antagonism. Renal endothelial function was tested using isolated renal interlobar arteries in a pressure myograph, which were exposed to acetylcholine or sodium nitroprusside.. Vasodilatory responses to the endothelial-dependent agonist acetylcholine were impaired in AT1-AA rats (74 [10]%) compared with normal pregnant controls (95 [5]%, P < 0.05). In the presence of ET(A) receptor antagonism, no differences were observed between controls or the AT1-AA treated group with regard to endothelial-dependent (acetylcholine) relaxation.. AT1-AA induced hypertension during pregnancy was associated with disparate renal endothelial responses to acetylcholine. The difference in renal vascular responses between AT1-AA and normal pregnant rats was abolished by ET(A) receptor blockade.

Topics: Animals; Autoantibodies; Disease Models, Animal; Endothelin A Receptor Antagonists; Endothelin-1; Female; Hypertension, Pregnancy-Induced; Hypertension, Renal; Kidney; Pregnancy; Pregnancy, Animal; Pyrrolidines; Rats; Rats, Sprague-Dawley; Receptor, Angiotensin, Type 1

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

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

Inflammatory cytokines such as tumor necrosis factor-alpha (TNF-alpha) may be an important link between placental ischemia and hypertension in preeclampsia. We examined the effect of 17-hydroxyprogesterone caproate (17-OHP) on TNF-alpha-stimulated endothelin (ET) production and hypertension during pregnancy.. TNF-alpha-stimulated ET was examined from endothelial cells cultured in the presence and absence of progesterone. Blood pressure and tissue ET-1 were measured in the following groups of pregnant rats: controls, 17-OHP (3.32 mg/kg), TNF-alpha treated (50 ng/day), TNF-alpha treated+17-OHP.. Progesterone abolished TNF-alpha-stimulated ET-1 from endothelial cells. TNF-alpha-induced hypertension was associated with significant increases in renal and placental ET-1. Administration of 17-OHP attenuated TNF-alpha-induced hypertension and decreased renal ET-1.. Progesterone directly abolished TNF-alpha-stimulated ET-1 and attenuated TNF-alpha-induced hypertension, possibly via suppression of the renal ET-1 system. These data suggest that treatment with progesterone of hypertension associated with elevated cytokines during pregnancy may be worthy of further consideration.

Topics: 17-alpha-Hydroxyprogesterone; Animals; Antihypertensive Agents; Blood Pressure Determination; Cells, Cultured; Disease Models, Animal; Endothelial Cells; Endothelin-1; Female; Humans; Hypertension, Pregnancy-Induced; Pregnancy; Rats; Rats, Sprague-Dawley; Tumor Necrosis Factor-alpha

Vascular resistance and blood pressure (BP) are reduced during late normal pregnancy (Norm-Preg). In contrast, studies in human preeclampsia and in animal models of hypertension in pregnancy (HTN-Preg) have suggested that localized reduction in uterine perfusion pressure (RUPP) in late pregnancy is associated with increased systemic vascular resistance and BP; however, the vascular mechanisms involved are unclear. Because Ca2+ is a major determinant of vascular contraction, we hypothesized that the intracellular free calcium concentration ([Ca2+]i) signaling of vasoconstriction is differentially regulated in systemic microvessels during normal and RUPP in late pregnancy. Pressurized mesenteric microvessels from Norm-Preg and RUPP rats were loaded with fura 2 in preparation for simultaneous measurement of diameter and [Ca2+]i (presented as fura 2 340/380 ratio). Basal [Ca2+]i was lower in RUPP (0.73 +/- 0.03) compared with Norm-Preg rats (0.82 +/- 0.03). Membrane depolarization by 96 mM KCl, phenylephrine (Phe, 10(-5) M), angiotensin II (ANG II, 10(-7) M), or endothelin-1 (ET-1, 10(-7) M) caused an initial peak followed by maintained vasoconstriction and [Ca2+]i. KCl caused similar peak vasoconstriction and [Ca2+]i in Norm-Preg (45.5 +/- 3.3 and 0.89 +/- 0.02%) and RUPP rats (46.3 +/- 2.1 and 0.87 +/- 0.01%). Maximum vasoconstriction to Phe, ANG II, and ET-1 was not significantly different between Norm-Preg (28.6 +/- 4.8, 32.5 +/- 6.3, and 40 +/- 4.6%, respectively) and RUPP rats (27.8 +/- 5.9, 34.4 +/- 4.3, and 38.8 +/- 4.1%, respectively). In contrast, the initial Phe-, ANG II-, and ET-1-induced 340/380 ratio ([Ca2+]i) was reduced in RUPP (0.83 +/- 0.02, 0.82 +/- 0.02, and 0.83 +/- 0.03, respectively) compared with Norm-Preg rats (0.95 +/- 0.04, 0.93 +/- 0.01, and 0.92 +/- 0.02, respectively). Also, the [Ca2+]i-vasoconstriction relationship was similar in KCl-treated but shifted to the left in Phe-, ANG II-, and ET-1-treated microvessels of RUPP compared with Norm-Preg rats. The lower agonist-induced [Ca2+]i signal of vasoconstriction and the leftward shift in the [Ca2+]i-vasoconstriction relationship in microvessels of RUPP compared with Norm-Preg rats suggest activation of [Ca2+]i sensitization pathway(s). The similarity in vasoconstriction in RUPP and Norm-Preg rats suggests that such a [Ca2+]i sensitization pathway(s) may also provide a feedback effect on Ca2+ mobilization/homeostatic mechanisms to protect against excessive vasoconstriction in system

Topics: Angiotensin II; Animals; Calcium Signaling; Disease Models, Animal; Endothelin-1; Feedback, Physiological; Female; Hypertension, Pregnancy-Induced; Litter Size; Mesentery; Microcirculation; Muscle, Smooth, Vascular; Phenylephrine; Potassium Chloride; Pregnancy; Rats; Rats, Sprague-Dawley; Splanchnic Circulation; Uterus; Vasoconstriction; Vasoconstrictor Agents

Reductions in uterine perfusion pressure (RUPP) in pregnant rats is associated with increased tumor necrosis factor-alpha (TNF-alpha). This study was designed to determine the role of endogenous TNF-alpha in mediating changes in arterial pressure and endothelin-1 (ET-1) in RUPP rats. To achieve this goal we examined the effect of RUPP in the presence and absence of a TNF-alpha-soluble receptor, etanerecept (0.4 mg/kg). Mean arterial pressure increased from 102+/-1 mm Hg in normal pregnant (NP) rats to 134+/-3 mm Hg (P<0.05) in RUPP rats. Serum TNF-alpha increased to 40+/-7.6 pg/mL in RUPP rats (n=24) versus 14.8+/-3.3 pg/mL (n=16; P<0.05) in NP rats. Administration of etanerecept decreased TNF-alpha in RUPP rats (n=20) to 17.2+/-3 pg/mL and mean arterial pressure to 118+/-2 mm Hg (P<0.05). Tissue ET-1 decreased in etanerecept-treated RUPP rats compared with control RUPP rats. The direct effect of TNF-alpha blockade on endothelial activation in response to placental ischemia was examined in human umbilical vein endothelial cells. ET-1 secreted from human umbilical vein endothelial cells treated with RUPP serum was 59.2+16 pg/mg and decreased when etanerecept was added to the medium with RUPP serum (7.60+/-0.77 pg/mg), as well as in response to serum from etanerecept-treated RUPP rats (7.30+/-0.55 pg/mg; P<0.001). ET-1 secreted from human umbilical vein endothelial cells was 15.6+/-2 pg/mg when treated with NP serum. These data support the hypothesis that endogenous TNF-alpha is an important stimulus for ET-1 in response to placental ischemia and is important in mediating endothelial cell activation and hypertension during pregnancy.

Topics: Animals; Birth Weight; Blood Pressure; Cells, Cultured; Endothelial Cells; Endothelin-1; Etanercept; Female; Humans; Hypertension, Pregnancy-Induced; Immunoglobulin G; Immunologic Factors; Ischemia; Kidney; Organ Size; Placenta; Pregnancy; Rats; Rats, Sprague-Dawley; Receptors, Tumor Necrosis Factor; RNA, Messenger; Tumor Necrosis Factor-alpha; Umbilical Veins; Uterus

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

Expression of endogenous ouabain in placenta and the concentrations of serum ET-1 and NO were examined in 30 patients with hypertensive disorder complicating pregnancy (HDCP) and 30 healthy pregnant women to investigate the effect of endogenous ouabain on HDCP. Compared with the healthy pregnant group, the expression of endogenous ouabain dramatically increased in the HDCP groups (P<0.01). There was a significantly positive correlation between the expression of endogenous ouabain with ET-1 (r=0.5567, P<0.01), while the correlation of endogenous ouabain and NO was significantly negative (r=-0.6895, P<0.01). As expected, the correlation between ET-1 and NO was negative (r=-0.7796, P<0.01). ET-1 concentrations of maternal and cord sera in HDCP groups were significantly higher in comparison with healthy pregnant group (P<0.01). On the contrast, NO concentrations were much lower in the maternal and cord sera of HDCP groups as compared with healthy pregnant group (P<0.01). Our data suggest that endogenous ouabain is directly involved in the nosogenesis of HDCP, with accompanying decreased NO and the elevated of ET-1.

Topics: Adult; Case-Control Studies; Endothelin-1; Female; Humans; Hypertension, Pregnancy-Induced; Nitric Oxide; Ouabain; Placenta; Pregnancy