endothelin-1 and Fetal-Growth-Retardation

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

It is well known that adverse conditions during intrauterine life, such as intrauterine growth restriction (IUGR), can result in permanent changes in the physiology and metabolism of the newborn, which in turn leads to an increased risk of disease in adulthood (fetal origin of adult disease hypothesis). In the first part of this review the epidemiological studies in which a correlation between low birth weight and chronic pathologies in adulthood was observed are reported. The second part of the review is focused on metabolomics studies that have revealed an altered metabolism in IUGR patients compared to controls. Together with more classic biomarkers of IUGR, such as endothelin-1, leptin, protein S100B and visfatin, the new holistic metabolomics approach has assumed a crescent role in the identification of disorders in the neonatal metabolic profile, determined by the interconnection of the different processes.

Topics: Biomarkers; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Endothelin-1; Epigenomics; Female; Fetal Growth Retardation; Fetal Nutrition Disorders; Genotype; Humans; Infant, Low Birth Weight; Infant, Newborn; Leptin; Metabolomics; Phenotype; Pregnancy; Prenatal Exposure Delayed Effects; Risk Factors

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

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

The environmental hypoxia of high altitude (HA) increases the incidence of intrauterine growth restriction (IUGR) approximately threefold. The peroxisome proliferator-activated receptor γ (PPAR-γ), a ligand-activated nuclear receptor that promotes vasorelaxation by increasing nitric oxide and downregulating endothelin-1 (ET-1) production, has been implicated in IUGR. Based on our prior work indicating that pharmacologic activation of the PPARγ pathway protects against hypoxia-associated IUGR, we used an experimental murine model to determine whether such effects may be attributed to vasodilatory effects in the uteroplacental circulation. Using wire myography, ex vivo vasoreactivity studies were conducted in uterine arteries (UtA) isolated from pregnant mice exposed to hypoxia or normoxia from gestational day 14.5 to 18.5. Exposure to troglitazone, a high-affinity PPARγ agonist-induced vasorelaxation in UtA preconstricted with phenylephrine, with HA-UtA showing increased sensitivity. Troglitazone blunted ET-1-induced contraction of UtA in hypoxic and normoxic dams equivalently. Immunohistological analysis revealed enhanced staining for ET-1 receptors in the placental labyrinthine zone in hypoxic compared to normoxic dams. Our results suggest that pharmacologic PPAR-γ activation, via its vasoactive properties, may protect the fetal growth under hypoxic conditions by improving uteroplacental perfusion and thereby justify further investigation into PPARγ as a therapeutic target for IUGR in pregnancies complicated by hypoxia.

Topics: Animals; Disease Models, Animal; Endothelin-1; Female; Fetal Growth Retardation; Hypoxia; Immunohistochemistry; Mice; Phenylephrine; Placenta; PPAR gamma; Pregnancy; Thiazolidinediones; Troglitazone; Uterine Artery

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

Intrauterine growth restriction (IUGR) is a major risk factor for perinatal morbidity and mortality, leading to long-term adverse cardiovascular outcomes. The present study aimed to investigate the potential mechanisms in IUGR-associated vascular endothelial dysfunction.. Human umbilical vein endothelial cells (HUVECs) were derived from IUGR or normal newborns. We found that the proliferation of IUGR-derived HUVECs was accelerated compared to those from normal subjects. Gene profiles related to vascular function including vasomotion, oxidative stress, and angiogenesis were dysregulated in IUGR-HUVECs. Compared with HUVECs from normal newborns, nitric oxide (NO) production was reduced, with imbalance between endothelial nitric oxide synthase (eNOS) and arginase-2 (Arg-2) in IUGR. Meanwhile, intracellular asymmetric dimethylarginine (ADMA) level was elevated with diminished dimethylarginine dimethylaminohydrolase 1 (DDAH1) expression in IUGR-HUVECs. Furthermore, endothelin-1 (ET-1) and hypoxia-inducible factor 1α (HIF-1α) expression were increased, and endothelin receptor type-B (ET. The present study demonstrated that the reduction of NO bioavailability and release results from elevated Arg-2, accumulation of intracellular ADMA, and imbalance of ET-1 and ET

Topics: Adult; Amidohydrolases; Arginase; Arginine; Case-Control Studies; Cell Proliferation; Cells, Cultured; Endothelin-1; Female; Fetal Growth Retardation; Gene Expression Regulation; Human Umbilical Vein Endothelial Cells; Humans; Infant, Newborn; Male; Neovascularization, Physiologic; Nitric Oxide; Nitric Oxide Synthase Type III; Oxidative Stress; Pregnancy; Protein-Arginine N-Methyltransferases; Receptor, Endothelin B; Repressor Proteins; Signal Transduction; Umbilical Veins

Intrauterine growth retardation/restriction (IUGR) is associated with fetal malnutrition. It has consequences for later life including increased incidence of obesity, diabetes mellitus, cardiovascular disease (CVD), and metabolic syndrome. Adipokines (adiponectin and leptin), adropin, and endothelin-1 are associated with obesity and metabolic syndrome regulation. Intrauterine changes in these mediators could affect programming of later adult obesity and metabolic syndrome. Our objectives were to compare the levels of these mediators in both cord and maternal blood between IUGR pregnancies and control, healthy pregnancies, and to study the correlation of adipokines with adropin and endothelin-1 in maternal and cord blood in IUGR pregnancies as well as in healthy control pregnancies. Maternal and cord blood samples were taken from 16 women with IUGR pregnancies and 16 women with healthy pregnancies. Serum levels of leptin, adiponectin, adropin, and endothelin-1 were measured by ELISA. Maternal blood adropin levels were significantly lower in the IUGR group than in the control group; the other mediators did not differ significantly. There was a positive correlation between maternal blood adropin and endothelin levels. (r=0.731, P=0.001) in the control but not the IUGR group. Cord blood adropin and adiponectin levels were significantly lower in the IUGR group compared with the control group, while leptin or endothelin-1 did not differ significantly. There was a negative correlation between adropin and leptin (r=-0.704, P=0.001) in the IUGR but not the control group cord blood. There were also positive correlations between endothelin and adropin for both groups (r=0.594, P=0.006; r=0.560, P=0.010, respectively); to the best of our knowledge, this is the first report of such a correlation. Differences in fetal expression of adropin and adiponectin in IUGR could influence programming of obesity, metabolic syndrome, diabetes, and CVD in later life.

Topics: Adiponectin; Adolescent; Adult; Biomarkers; Blood Proteins; Case-Control Studies; Endothelin-1; Enzyme-Linked Immunosorbent Assay; Female; Fetal Blood; Fetal Growth Retardation; Humans; Infant, Newborn; Intercellular Signaling Peptides and Proteins; Leptin; Peptides; Pregnancy; Prospective Studies; Young Adult

Fetal growth restriction (FGR) is commonly associated with perinatal morbidity and mortality. Nitric oxide (NO) deficiency increases endothelin-1 (ET-1) production, and this increased ET-1 may contribute to the pathophysiology of NO deficiency-induced FGR. Using an endothelial NO synthase knockout mouse model of FGR, we sought to determine (a) the relative importance of maternal versus conceptus (fetal and placental) NO deficiency and (b) the contribution of ET-1 to the pathogenesis of FGR in this model. Fetal growth restriction occurred both with NO-deficient conceptuses in the setting of maternal NO production and with maternal NO deficiency in the setting of NO-producing conceptuses. Placental ET-1 expression was increased in NO-deficient dams, ET receptor A (ETA) production increased in endothelial nitric oxide synthase(+/-) placentas, and antagonism of ETA prevented FGR. These results demonstrate that both maternal and conceptus NO deficiency can contribute to FGR and suggest a role for ETA antagonists as therapeutic agents in FGR.

Topics: Animals; Endothelin A Receptor Antagonists; Endothelin-1; Female; Fetal Development; Fetal Growth Retardation; Fetal Weight; Maternal-Fetal Exchange; Mice; Mice, Knockout; Nitric Oxide Synthase Type III; Placenta; Pregnancy; Pyrrolidines; Receptor, Endothelin A; RNA, Messenger

Renal failure is common in the NICU; Acute Kidney Injury (AKI) occurs in 8-24% of admissions. Although AKI is preventable with early diagnosis, no reliable AKI biomarkers exist. Endothelin-1 (ET-1) has been implicated in renal pathogenesis, and elevated urinary ET-1 (uET-1) levels may correlate with progression of renal dysfunction. The study objectives were to determine whether uET-1 levels correlate with renal function parameters and/or fetal growth restriction, and if uET-1 is a potential neonatal AKI biomarker.. Sixty-three neonates were enrolled and divided into gestational age (GA) groups by weeks: 1) (24-30 6/7; n = 24); 2) (31-36 6/7; n = 26); and 3) (37-42; n = 13). Additional preterm subgroups for fetal growth restriction analysis included: 1) Appropriate for GA (AGA; n = 40), and 2) Small for GA (SGA; n = 10). ET-1 levels, measured using enzyme linked immunosorbent assay, were collected at birth (cord blood) and 24 h ( ± 4) of life (blood/urine).. No correlation was found between uET-1 and blood plasma levels at birth (r = 0.15; p > 0.05) or 24 h (r = 0.17; p > 0.05). uET-1 negatively correlated with GA (r = -0.44; p < 0.001) and GFR (r = -0.34; p < 0.01). uET-1 levels did not correlate with creatinine (r = 0.13; p > 0.05), BUN (r = 0.19; p > 0.05), BUN/Cr ratio (r = 0.15; p > 0.05), or urinary output (r = 0.12; p > 0.05). In fetal growth restriction subgroup analyses: uET-1 levels negatively correlated with GFR in the PT-AGA subgroup (r = -0.38; p = 0.017), but not with PT-SGA (r = 0.01; p > 0.05).. Plasma and uET-1 levels did not correlate; therefore, renal ET-1 excretion may reflect renal ET-1 production. uET-1 levels correlated negatively with GA and GFR. uET-1 may be a marker of impaired neonatal circulatory regulation and consequent renal injury.

Topics: Acute Kidney Injury; Biomarkers; Birth Weight; Creatinine; Endothelin-1; Enzyme-Linked Immunosorbent Assay; Female; Fetal Blood; Fetal Growth Retardation; Gestational Age; Humans; Infant, Newborn; Male; Pilot Projects; Predictive Value of Tests; Pregnancy; Prospective Studies; United States

The renal endothelin system contributes to sex differences in blood pressure with males demonstrating greater endothelin type-A receptor-mediated responses relative to females. Intrauterine growth restriction programs hypertension and enhance renal sensitivity to acute angiotensin II in male growth-restricted rats. Endothelin is reported to work synergistically with angiotensin II. Thus, this study tested the hypothesis that endothelin augments the blood pressure response to acute angiotensin II in male growth-restricted rats. Systemic and renal hemodynamics were determined in response to acute angiotensin II (100 mg/kg per minute for 30 minutes) with and without the endothelin type-A receptor antagonist, Atrasentan (ABT-627; 10 ng/kg per minute for 30 minutes), in rats pretreated with enalapril (250 mg/L for 1 week) to normalize the endogenous renin-angiotensin system. Endothelin type-A receptor blockade reduced angiotensin II-mediated increases in blood pressure in male control and male growth-restricted rats. Endothelin type-A receptor blockade also abolished hyper-responsiveness to acute angiotensin II in male growth-restricted rats. Yet, blood pressure remained significantly elevated above baseline after endothelin type-A receptor blockade, suggesting that factors in addition to endothelin contribute to the basic angiotensin II-induced pressor response in male rats. We also determined sex-specific effects of endothelin on acute angiotensin II-mediated hemodynamic responses. Endothelin type-A receptor blockade did not reduce acute angiotensin II-mediated increases in blood pressure in female control or growth-restricted rats, intact or ovariectomized. Thus, these data suggest that endothelin type-A receptor blockade contributes to hypersensitivity to acute angiotensin II in male growth-restricted rats and further supports the sex-specific effect of endothelin on blood pressure.

Topics: Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Atrasentan; Blood Pressure; Blotting, Western; Enalapril; Endothelin Receptor Antagonists; Endothelin-1; Female; Fetal Growth Retardation; Glomerular Filtration Rate; Hemodynamics; Kidney; Male; Ovariectomy; Pregnancy; Pyrrolidines; Rats; Receptor, Endothelin A; Receptor, Endothelin B; Reverse Transcriptase Polymerase Chain Reaction; Sex Factors

Epidemiological studies have revealed that intrauterine growth retardation (IUGR) or low birth weight is linked to the later development of asthma. Epigenetic regulatory mechanisms play an important role in the fetal origins of adult disease. However, little is known regarding the correlation between epigenetic regulation and the development of asthma following IUGR.. An IUGR and ovalbumin (OVA)-sensitization/challenge rat model was used to study whether epigenetic mechanisms play a role in the development of asthma following IUGR.. Maternal nutrient restriction increased histone acetylation levels of the endothelin-1 (ET-1) gene promoter in lung tissue of offspring, but did not cause significant alterations of DNA methylation. The effect was maintained until 10 weeks after birth. Furthermore, these epigenetic changes may have induced IUGR individuals to be highly sensitive to OVA challenge later in life, resulting in more significant changes related to asthma.. These findings suggest that epigenetic mechanisms might be closely associated with the development of asthma following IUGR, providing further insight for improved prevention of asthma induced by environmental factors.

Topics: Acetylation; Age Factors; Allergens; Animals; Asthma; Bronchial Hyperreactivity; Disease Models, Animal; DNA Methylation; Endothelin-1; Epigenesis, Genetic; Female; Fetal Growth Retardation; Gene Expression Regulation; Genetic Predisposition to Disease; Histones; Maternal Nutritional Physiological Phenomena; Nutritional Status; Ovalbumin; Pregnancy; Promoter Regions, Genetic; Rats, Sprague-Dawley; Risk Factors

Accumulating evidence reveals that intrauterine growth retardation (IUGR) can cause varying degrees of pulmonary arterial hypertension (PAH) later in life. Moreover, epigenetics plays an important role in the fetal origin of adult disease. The goal of this study was to investigate the role of epigenetics in the development of PAH following IUGR.. The IUGR rats were established by maternal undernutrition during pregnancy. Pulmonary vascular endothelial cells (PVEC) were isolated from the rat lungs by magnetic-activated cell sorting (MACS). We investigated epigenetic regulation of the endothelin-1 (ET-1) gene in PVEC of 1-day and 6-week IUGR rats, and response of IUGR rats to hypoxia.. The maternal nutrient restriction increased the histone acetylation and hypoxia inducible factor-1α (HIF-1α) binding levels in the ET-1 gene promoter of PVEC in IUGR newborn rats, and continued up to 6 weeks after birth. These epigenetic changes could result in an IUGR rat being highly sensitive to hypoxia later in life, causing more significant PAH or pulmonary vascular remodeling.. These findings suggest that epigenetics is closely associated with the development of hypoxic PAH following IUGR, further providing a new insight for improved prevention and treatment of IUGR-related PAH.

Topics: Acetylation; Actins; Age Factors; Animals; Animals, Newborn; Binding Sites; Blood Pressure; Cell Separation; Disease Models, Animal; Endothelial Cells; Endothelin-1; Epigenesis, Genetic; Familial Primary Pulmonary Hypertension; Female; Fetal Growth Retardation; Flow Cytometry; Histones; Hypertension, Pulmonary; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit; Lung; Pregnancy; Promoter Regions, Genetic; Pulmonary Artery; Rats; Rats, Sprague-Dawley

Prenatal hypoxia can alter the growth trajectory of the fetus and cause lasting health complications including vascular dysfunction. We hypothesized that offspring that were intrauterine growth restricted (IUGR) because of prenatal hypoxia would exhibit altered vascular endothelin-1 (ET-1) signaling in later life. Isolated mesenteric artery responses to big ET-1 (bET-1) and ET-1 were assessed by using wire myography. Male IUGR offspring had 3-fold greater bET-1-induced vasoconstriction compared with controls (n=7 per group; P<0.001); NO synthase inhibition with L-N(G)-nitro-arginine-methyl ester potentiated bET-1-induced vasoconstriction, albeit this effect was 2-fold greater (P<0.05) in male control compared with IUGR offspring. Vascular responses to bET-1 were similar between female IUGR and control offspring (n=9-11 per group). In the presence of L-N(G)-nitro-arginine-methyl ester, pretreatment with the chymase inhibitor chymostatin, the gelatinase inhibitor GM6001, or the neutral endopeptidase inhibitor thiorphan did not alter responses to bET-1; however, the ET-converting enzyme inhibitor CGS35066 almost completely abolished vascular responses to bET-1 in control and IUGR groups. Systolic blood pressure in IUGR male offspring was more responsive to ET-1 antagonism in vivo compared with controls (-9 versus -4 mm Hg; n=5 per group; P=0.02); no such differences were observed in female offspring (n=5-6 per group). These results demonstrate that vascular ET-1 function is programmed by prenatal hypoxia and provide further insights into the sex differences in the long-term vascular effects of developmental stressors.

Topics: Animals; Blood Pressure; Dose-Response Relationship, Drug; Endothelin-1; Endothelium, Vascular; Female; Fetal Growth Retardation; Hypoxia; Male; Mesenteric Arteries; Nitric Oxide; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Rats, Sprague-Dawley; Sex Factors; Vasoconstriction

Topics: Animals; Endothelin-1; Female; Fetal Growth Retardation; Hypoxia; Male; Mesenteric Arteries; Pregnancy; Prenatal Exposure Delayed Effects

The significance of endothelin-1 (ET-1) in platelet-activating factor (PAF)-induced fetal growth restriction (FGR) was evaluated in timed-pregnant rats receiving intravenous carbamyl-PAF (c-PAF; 0.5, 1.0, or 2.5 µg/kg per h) or vehicle, with or without ET-1 receptor A (ET(A)) antagonist (10 or 20 mg/kg per d) for 7 days beginning on gestation day 14. Tissues were collected on day 21. Carbamyl-PAF reduced fetal weights dose dependently. Placental weights were significantly reduced but not dose dependently. ET(A) antagonism prevented FGR at the 0.5, but not the 1.0 and 2.5 µg/kg per h c-PAF doses. Correspondingly, placental, but not uterine, preproET-1 messenger RNA (mRNA) expression (determined by reverse transcription-polymerase chain reaction) was increased at 0.5 µg/kg per h but not at higher c-PAF doses. In summary, c-PAF infusion results in fetal and placental growth restriction in the rat. At low doses of c-PAF, ET-1 is central to the pathophysiology of PAF-induced FGR. At higher c-PAF doses, FGR is induced by mechanisms other than ET-1 action.

Topics: Animals; Endothelin A Receptor Antagonists; Endothelin-1; Female; Fetal Growth Retardation; Fetal Weight; Gene Expression; Organ Size; Placenta; Platelet Activating Factor; Pregnancy; Pregnancy Outcome; Rats; Rats, Sprague-Dawley; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger

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

To compare venous cord plasma concentrations of 4 vasoactive peptide precursors: carboxy-terminal proarginine vasopressin, CT-prondothelin (ET)-1, midregional proadrenomedullin, and MR-proatrial natriuretic peptide, between fetuses with intrauterine growth restriction and appropriate for gestational age controls.. Matched-pair analysis of 12 fetuses with significant intrauterine growth restriction and 42 healthy appropriate for gestational age control fetuses. All infants were singletons, delivered by elective section after 34 weeks and without chromosomal abnormalities.. Umbilical cord plasma copeptin levels (median [range]) were 4-fold higher in intrauterine growth restriction infants than in matched appropriate for gestational age controls: 23.2 (6.7-449) vs 5.1 (2.5-53) pmol/L (P < .001). Multivariate regression analysis revealed an association between copeptin and umbilical artery resistance index z-score (P = .034). The 3 other precursor peptides showed no changes.. High copeptin concentrations in the cord blood of intrauterine growth restriction newborns reflect a fetal stress response and support the fetal programming hypothesis.

Topics: Adult; Arginine Vasopressin; Atrial Natriuretic Factor; Biomarkers; Case-Control Studies; Endothelin-1; Female; Fetal Blood; Fetal Distress; Fetal Growth Retardation; Glycopeptides; Humans; Middle Aged; Peptide Fragments; Young Adult

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 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

Reduced uteroplacental blood flow is hypothesized to play a key role in altitude-associated fetal growth restriction. It is unknown whether reduced blood flow is a cause or consequence of reduced fetal size. We asked whether determinants of uteroplacental blood flow were altered prior to reduced fetal growth and whether vasoactive and/or angiogenic factors were involved. Women residing at low (LA; 1,600 m, n = 18) or high altitude (HA; 3,100 m, n = 25) were studied during pregnancy (20, 30, and 36 wk) and 4 mo postpartum (PP) using Doppler ultrasound. In each study, endothelin (ET-1), nitric oxide metabolites (NO(x)), soluble fms-like tyrosine kinase (sFlt-1) and placental growth factor (PlGF) levels were quantified. At HA, birth weights were lower (P < 0.01) and small-for-gestational age was more common (P < 0.05) compared with LA. HA was associated with lower uterine artery (UA) diameter (P < 0.01) and blood flow (P < 0.05). Altitude did not affect ET-1, sFlt-1 or PlGF; however, ET-1/NO(x) was greater and NO(x) lower during pregnancy and PP at HA vs. LA. ET-1/NO(x) was negatively associated with birth weight (20 wk, P < 0.01; 36 wk, P = 0.05) at LA and HA combined. At HA, UA blood flow (30 wk) was positively associated with birth weight (dagger). UA blood flow and ET-1/NO(x) levels accounted for 45% (20 wk) and 32% (30 wk) of birth weight variation at LA and HA combined, primarily attributed to effects at HA. We concluded that elevated ET-1/NO(x) and altered determinants of uteroplacental blood flow occur prior to altitude-associated reductions in fetal growth, and therefore, they are likely a cause rather than a consequence of smaller fetal size.

Topics: Adult; Altitude; Birth Weight; Colorado; Endothelin-1; Female; Femur; Fetal Growth Retardation; Head; Humans; Infant, Newborn; Infant, Small for Gestational Age; Nitric Oxide; Oxygen; Pregnancy; Regression Analysis; Uterus

The purpose of this prospective study was to record endothelin-1 (ET-1) concentrations in the second trimester amniotic fluid and compare these values in women who developed intrauterine growth restriction (IUGR) later in pregnancy with those with uneventful pregnancies.. Amniotic fluid was retrieved by amniocentesis from 125 women in the second trimester of pregnancy. The levels of ET1 were measured by a sensitive and specific radioimmunoassay.. From the 125 women included in the study 12 had pregnancies that later developed IUGR and 88 had uneventful pregnancies. The ET1 concentration was significantly higher (P<0.005) in women who later developed IUGR than in normal pregnancy (106 pg/ml versus 64.7 pg/ml).. The amniotic fluid concentration of ET1 is elevated by the second trimester in women who later develop IUGR.

Topics: Adult; Amniotic Fluid; Biomarkers; Case-Control Studies; Endothelin-1; Female; Fetal Growth Retardation; Humans; Pregnancy; Pregnancy Trimester, Second; Prospective Studies

The objective of the study was to evaluate the role of endothelin-1 and platelet-activating factor in ischemia/reperfusion-induced fetal growth restriction in the rat.. On day 17 of gestation, the right uterine and ovarian arteries were occluded for 30 minutes in experimental but not sham-operated rats. All rats received endothelin receptor A antagonist, A-127722 (10 mg/kg per day), platelet-activating factor antagonist, WEB-2086 (1 mg/kg), or vehicle. On gestational day 21, litter size, fetal viability, and fetal and placental weights were recorded. Reverse transcription-polymerase chain reaction for phospholipase A2-IIA and preproendothelin-1 messenger ribonucleic acid was performed on uterus and placentas from each uterine horn. Groups were compared statistically by analysis of variance.. Ischemia/reperfusion reduced fetal weights, in both the ischemic horn and the nonischemic horn (P < .001). Antagonism of either endothelin receptor A or platelet-activating factor normalized fetal growth in both horns. Neither placental weight nor the incidence of fetal demise was affected by ischemia/reperfusion. Phospholipase A2-IIA and preproendothelin-1 messenger ribonucleic acid expression did not differ between right and left uterine horns in any group. Uterine and placental tissues in the ischemia/reperfusion group exhibited increased phospholipase A2-IIA (P < .01) but not preproendothelin-1.. Endothelin-1 and platelet-activating factor are both important mediators in the pathophysiology of ischemia/reperfusion-induced fetal growth restriction in the rat, contributing to the fetal growth restriction observed in both the ischemic and nonischemic horns. Antagonism of either mediator produces normal fetal growth in this model of fetal growth restriction.

Topics: Animals; Endothelin Receptor Antagonists; Endothelin-1; Female; Fetal Growth Retardation; Fetal Weight; Isoenzymes; Male; Ovary; Phospholipases A; Phospholipases A2; Placenta; Platelet Activating Factor; Protein Isoforms; Rats; Rats, Sprague-Dawley; Reperfusion Injury; RNA, Messenger; Uterus

The aim of the present study was to evaluate a rat model of placental dysfunction/preeclampsia in pregnancies complicated by maternal diabetes. A second objective was to evaluate the effects of vitamin E treatment in this model.. Normal and streptozotocin-induced diabetic rats of two different strains (U and H) were given intraperitoneal (IP) injections of the angiogenesis inhibitor Suramin (Sigma Chemical Co, St Louis, MO) or saline in early pregnancy, and fed standard or vitamin E-enriched food. The outcome of pregnancy was evaluated on gestational day 20.. In both rat strains Suramin caused fetal growth retardation, decreased placental blood flow, and increased placental concentration of the isoprostane 8-iso-PGF(2alpha). In the U rats Suramin also caused increased fetal resorption rate, increased maternal blood pressure, decreased renal blood flow, and diminished maternal growth. Diabetes caused severe maternal and fetal growth retardation, increased resorption rate, and increased placental 8-iso-PGF(2alpha) concentration independent of Suramin administration. The maternal and fetal effects of Suramin and diabetes were more pronounced in the U strain than in the H strain. Vitamin E treatment improved the status of Suramin-injected diabetic rats: in U rats the blood pressure increase was normalized; and in both U and H rats the decreased placental blood flow was marginally enhanced, and the increase in placental 8-iso-PGF(2alpha) was partly normalized by vitamin E.. Suramin injections to pregnant rats cause a state of placental insufficiency, which in U rats resembles human preeclampsia. The induction of this condition is at least partly mediated by oxidative stress, and antagonized by antioxidative treatment. Maternal diabetes involves increased oxidative stress, and causes both maternal and fetal morbidity, which are only marginally affected by additional Suramin treatment.

Topics: Animals; Antioxidants; Blood Pressure; Body Weight; Diabetes Mellitus, Experimental; Electrolytes; Endothelin-1; Female; Fetal Growth Retardation; Fetal Resorption; Isoprostanes; Lipids; Nitrites; Perfusion; Placenta; Pregnancy; Pregnancy in Diabetics; Pregnancy Outcome; Rats; Rats, Sprague-Dawley; Suramin; Vitamin E

Normal placental function is dependent on maintenance of uteroplacental perfusion. Endothelin, a potent vasoconstrictor, is produced in and is active in the uteroplacental vasculature. The purpose of this study was to determine the role of endothelin in the regulation of uteroplacental perfusion under normal conditions, and in hypoxia-induced fetal growth restriction.. Timed-pregnant Sprague-Dawley rats, outfitted with arterial catheters, were maintained in either a normoxic or a normobaric hypoxic (12% oxygen) atmosphere from day 18 to 21 of gestation. During this time, the endothelin receptor A antagonist, A-127722, or its vehicle was administered. Regional blood flow was determined on gestational day 21 using 57Co-labeled microspheres. Data were analyzed by analysis of variance with statistical significance accepted at P<.05.. Both placental and uterine placental bed perfusion were significantly decreased by hypoxia and returned to normal values with the endothelin antagonist (P<.01 and P<.05, respectively). Fetal weights were significantly lower in the hypoxic group (P<.001) and restored to control levels by the antagonist.. In the rat, endothelin contributes little to the regulation of uteroplacental perfusion under normal conditions. Hypoxia results in a decrease in perfusion of the uteroplacental bed and of the placenta, and perfusion in both of these beds is normalized by endothelin A receptor antagonism. We conclude that endothelin plays a primary role in the pathophysiology of hypoxia-induced fetal growth restriction by reducing uteroplacental perfusion.

Topics: Animals; Atrasentan; Blood Flow Velocity; Blood Pressure; Cobalt Radioisotopes; Endothelin A Receptor Antagonists; Endothelin-1; Female; Fetal Growth Retardation; Fetal Hypoxia; Fetus; Gestational Age; Kidney; Microspheres; Oxygen; Placenta; Pregnancy; Pyrrolidines; Rats; Rats, Sprague-Dawley; Uterus

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

To probe into therapeutic effect and its mechanism of "Huo Xue Bu Qi Fang" (HXBQF) on fetal rats with intrauterine growth retardation (IUGR).. The model of pregnant rat with IUGR was established by passive smoking method. Forty pregnant rats with IUGR were randomly divided into intervention group (with high-, middle- and low-dose Chinese traditional medicine) and non-intervention group. In addition, 10 normal pregnant rats were taken into control group. Intervention group was adminstered with 16.2, 5.4 and 1.62 g/kg HXBQF respectively. Non-intervention group and control group were administered with 10 ml/kg saline. Fetal rats were taken out, and blood and urine samples were collected from pregnant rats on day 21 of the pregnancy. The weight, nose-hip-length and poundera index of these fetal rats were measured. Serum NO, plasma ET-1 and urine 8-epi-PGF2 alpha level from pregnant rats were determined by nitro-reductase method, radioimmunoassay (RIA) and enzyme immunoassay (EIA) respectively.. Compared with fetal rats from non-intervention group, fetal weight, distance between nose-hip, poundera index serum NO level and NO/ET-1 were increased, plasma ET-1 level and urine 8-epi-PGF2 alpha level were decreased in those from intervention group (P < 0.01).. There is an enhancement of lipid peroxidation and NO/ET-1 ratio imbalance in pregnant rats with IUGR. HXBQF has good therapeutic effect on IUGR since it can inhibit lipid oxidation and regulate NO/ET-1 balance.

Topics: Animals; Antioxidants; Body Weight; Dinoprost; Drugs, Chinese Herbal; Endothelin-1; Female; Fetal Growth Retardation; Nitric Oxide; Pregnancy; Random Allocation; Rats; Rats, Sprague-Dawley

We have examined whether endothelin-1 (ET-1) and erythropoietin (EPO) in amniotic fluid, and EPO in fetal serum obtained by cordocentesis from fetuses with signs of intrauterine growth retardation (IUGR), were correlated to fetal growth and/or chronic fetal hypoxia.. Amniotic fluid and fetal serum were obtained by cordocentesis from 28 fetuses suspected to have IUGR and subsequently analyzed for EPO and ET-1 by ELISA. These data were correlated to blood gas results and fetal/maternal parameters at delivery.. A novel finding was that ET-1 correlated to PO2 in amniotic fluid. The average level of ET-1 in amniotic fluid was 48.3+/-4.7 pmol/L. The results also showed a correlation between EPO levels in amniotic fluid and EPO in fetal serum. Furthermore, EPO correlated weakly to birth weight at delivery. Children with the lowest birth weights had the highest EPO levels. High EPO values, similarly to ET-1, correlated to low pO2 values. The level of EPO in amniotic fluid was 8.0+/-1.6 mIU/ml and in cord blood 29.5+/-9.6 mIU/ml.. The results indicate that ET-1 levels may be a marker for short-term hypoxia, but not for fetal growth, since ET-1 in amniotic fluid was correlated to PO2 at the time of cordocentesis, but not to birth weight. The results also indicate that EPO levels in amniotic fluid and in fetal cord serum are highly correlated, and thus both can be used as markers for fetal growth and chronic hypoxia before the onset of labor.

Topics: Adult; Amniotic Fluid; Biomarkers; Blood Gas Analysis; Embryonic and Fetal Development; Endothelin-1; Erythropoietin; Female; Fetal Growth Retardation; Fetal Hypoxia; Humans; Pregnancy

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

The purpose of this study was to evaluate whether cordocentesis is associated with the release of vasoactive substances and whether there are differences between normally grown and growth-restricted fetuses.. 6-Keto-prostaglandin F1 alpha (the stable metabolite of prostacyclin), endothelin-1, and cyclic guanosine monophosphate were measured in fetal blood at the beginning and closing of cordocentesis in 30 normally grown fetuses and 25 growth-restricted fetuses. This latter group was characterized by abnormal Doppler index values in umbilical artery and middle cerebral artery, suggestive of chronic hypoxemia as the causative factor of the impaired growth. In six growth-restricted fetuses bradycardia occurred at the end of the procedure. Umbilical artery pulsatility index was measured by Doppler ultrasonography immediately before and after the procedure.. The median interval between the two blood samples obtained by cordocentesis was 90 seconds (range 60 to 320 seconds). During this interval a significant rise of 6-keto-prostaglandin F1 alpha (p < or = 0.0001) and endothelin-1 (p = 0.03) was evidenced in normally grown fetuses. The increase in 6-keto-prostaglandin F1 alpha was significantly related (r = 0.52, p = 0.002) to the fall of umbilical artery pulsatility index occurring after the procedure. In growth-restricted fetuses cordocentesis induced a marked increase of endothelin-1 (p = 0.0002), which was significantly related to the severity of acidosis (r = 0.52, p = 0.018), whereas no modifications were evidenced for the other agents tested. The increase of endothelin-1 was higher in those growth-restricted fetuses showing bradycardia at the end of the procedure than in growth-restricted fetuses that did not (p = 0.04). The variations of the vasoactive substances assayed were not significantly related to the type of procedure (transamniotic or transplacental), the amount of blood aspirated during the procedure, the interval elapsing between the first and second samples, the gestational age at which the procedure was performed, and the degree of fetal smallness.. Cordocentesis induces the rapid release of vasoactive substances and the effect differs between normally grown and growth-restricted fetuses. This may explain the different hemodynamic response and the higher rate of complications occurring in the latter group after cordocentesis.

Topics: 6-Ketoprostaglandin F1 alpha; Bradycardia; Cordocentesis; Cyclic GMP; Endothelin-1; Female; Fetal Blood; Fetal Growth Retardation; Gestational Age; Humans; Pregnancy; Pulsatile Flow; Umbilical Arteries

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

The purpose of this study was to measure cord blood endothelin-1,2 concentrations in growth-restricted infants with abnormal flow velocity waveforms.. Endothelin-1,2 concentrations were measured by radioimmunoassay in the cord blood of 16 growth-restricted infants with abnormal flow velocity waveforms before delivery, 16 growth-restricted infants with normal flow velocity waveforms before delivery, and 44 appropriately grown infants. Clinical data regarding pregnancy complications and neonatal outcome were collected.. The mean endothelin-1,2 concentration in growth-restricted infants with abnormal flow velocity waveforms (50.2 +/- 16.4 pg/ml) was significantly higher than in growth-restricted infants with normal flow velocity waveforms (33.3 +/- 14.2 pg/ml, p < 0.05) or in appropriately grown infants (25.8 +/- 9.7 pg/ml, p < 0.05). Oligohydramnios was also associated with elevated endothelin levels.. We conclude that endothelin-1,2 concentrations are elevated in growth-restricted infants with abnormal flow velocity waveforms and may play a role in the development of abnormal fetoplacental resistance.

Topics: Blood Flow Velocity; Endothelin-1; Endothelin-2; Endothelins; Female; Fetal Blood; Fetal Growth Retardation; Humans; Infant, Newborn; Osmolar Concentration; Placenta; Pregnancy; Regression Analysis; Ultrasonography, Prenatal; Vascular Resistance