adrenomedullin and Pre-Eclampsia

The immunology of pregnancy is complex and incompletely understood. Aberrant immune activity in the decidua and in the placenta is believed to play a role in diseases of pregnancy, such as infertility, miscarriage, fetal growth restriction and preeclampsia. Here, we briefly review the endocrine control of uterine natural killer cell populations and their functions by the peptide hormone adrenomedullin. Studies in genetic animal models have revealed the critical importance of adrenomedullin dosage at the maternal-fetal interface, with cells from both the maternal and fetal compartments contributing to essential aspects underlying appropriate uterine receptivity, implantation and vascular remodeling of spiral arteries. These basic insights into the crosstalk between the endocrine and immune systems within the maternal-fetal interface may ultimately translate to a better understanding of the functions and consequences of dysregulated adrenomedullin levels in clinically complicated pregnancies.

Topics: Adrenomedullin; Animals; Disease Models, Animal; Embryo Implantation; Endocrine System; Female; Humans; Immunity, Cellular; Killer Cells, Natural; Neovascularization, Physiologic; Pre-Eclampsia; Pregnancy

Preeclampsia is a leading cause of maternal and fetal/neonatal mortality and morbidity worldwide. The early identification of patients with an increased risk for preeclampsia is therefore one of the most important goals in obstetrics. The availability of highly sensitive and specific physiologic and biochemical markers would allow not only the detection of patients at risk but also permit a close surveillance, an exact diagnosis, timely intervention (e.g. lung maturation), as well as simplified recruitment for future studies looking at therapeutic medications and additional prospective markers. Today, several markers may offer the potential to be used, most likely in a combinatory analysis, as predictors or diagnostic tools. We present here the current knowledge on the biology of preeclampsia and review several biochemical markers which may be used to monitor preeclampsia in a future, that, we hope, is not to distant from today.

Topics: ADAM Proteins; ADAM12 Protein; Adrenomedullin; Angiogenesis Inducing Agents; Antigens, CD; Arteries; Autoantibodies; Biomarkers; C-Reactive Protein; Cytokines; DNA; Endoglin; Female; Fetus; Galectins; Humans; Membrane Proteins; Nicotinamide Phosphoribosyltransferase; P-Selectin; Placenta; Pre-Eclampsia; Pregnancy; Pregnancy Proteins; Pregnancy-Associated Plasma Protein-A; Prenatal Diagnosis; Receptor, Angiotensin, Type 1; Receptors, Cell Surface; Serum Amyloid P-Component; Ultrasonography, Doppler; Uterus

Topics: Adrenomedullin; Adult; Biomarkers; Central Nervous System; Female; Humans; Peptides; Pre-Eclampsia; Pregnancy; Regional Blood Flow; Sensitivity and Specificity

Topics: Adrenomedullin; Female; Humans; Peptides; Pre-Eclampsia; Pregnancy

Preeclampsia is a heterogeneous hypertensive disorder of pregnancy. It affects multiorgans and may lead to fetal growth restriction, organ failure, seizure, and maternal death. Unfortunately, current treatments are ineffective at delaying the progression of preeclampsia even for a few days. Clinicians are often forced to deliver preterm fetus if severe preeclampsia occurred early during pregnancy, leading to premature birth-associated complications. Preeclampsia has been associated with defects at the maternal-fetal interface and maternal vascular dysfunction. Of interest, the adrenomedullin peptide and its cognate receptors, calcitonin receptor-like receptor (CLR)/ receptor activity-modifying protein (RAMP) receptor complexes, have been shown to be important regulators of cardiovascular adaptation and feto-placental development during pregnancy. Although the exact role of adrenomedullin-CLR/RAMP signaling in different feto-maternal compartments during pregnancy and how adrenomedullin expression affects preeclampsia development remains to be clarified, we hypothesized that the sustained activation of CLR/RAMP receptors could be a promising strategy to mitigate placental ischemia-associated vascular dysfunction and fetal growth restriction under preeclampsia-like conditions.. To explore this possibility, we have developed a stable adrenomedullin analog, ADE101, and investigated its effects on human lymphatic microvascular endothelial (HLME) cell proliferation, hemodynamics, and pregnancy outcomes in pregnant rats with reduced uteroplacental perfusion pressure (RUPP) induced by clipping of uterine arteries on gestation day 14.. The ADE101 analog has a potent effect on CLR/RAMP2 receptor activation, and an enhanced stimulatory effect on HLME cell proliferation compared to wild-type peptides. ADE101 also exhibits a lasting effect on hemodynamics in normal and hypertensive rats. In addition, studies using the RUPP model showed that ADE101 significantly reduces placental ischemia-induced hypertension and fetal growth restriction in a dose-dependent manner. Infusion of ADE101 increased the weight of fetuses and placentas in RUPP animals to 252% and 202% of that of RUPP controls, respectively.. These data suggested that long-acting adrenomedullin analog could be useful for quenching hypertension as well as the vascular ischemia-associated organ damages in preeclamptic patients.

Topics: Adrenomedullin; Animals; Blood Pressure; Female; Fetal Growth Retardation; Humans; Hypertension; Ischemia; Placenta; Pre-Eclampsia; Pregnancy; Rats; Rats, Sprague-Dawley; Uterus

Early-onset preeclampsia (EOPE) is a severe pregnancy complication associated with defective trophoblast differentiation and functions at implantation, but manifestation of its phenotypes is in late pregnancy. There is no reliable method for early prediction and treatment of EOPE. Adrenomedullin (ADM) is an abundant placental peptide in early pregnancy. Integrated single-cell sequencing and spatial transcriptomics confirm a high ADM expression in the human villous cytotrophoblast and syncytiotrophoblast. The levels of ADM in chorionic villi and serum were lower in first-trimester pregnant women who later developed EOPE than those with normotensive pregnancy. ADM stimulates differentiation of trophoblast stem cells and trophoblast organoids in vitro. In pregnant mice, placenta-specific ADM suppression led to EOPE-like phenotypes. The EOPE-like phenotypes in a mouse PE model were reduced by a placenta-specific nanoparticle-based forced expression of ADM. Our study reveals the roles of trophoblastic ADM in placental development, EOPE pathogenesis, and its potential clinical uses.

Topics: Adrenomedullin; Animals; Cell Differentiation; Female; Humans; Mice; Placenta; Pre-Eclampsia; Pregnancy; Trophoblasts

Preeclampsia is a pregnancy complication associated with elevated placental secretion of anti-angiogenic factors, maternal endothelial dysfunction and end-organ injury. Adrenomedullin (ADM) is a pro-angiogenic peptide hormone which regulates blood pressure and vascular integrity. It is highly expressed in both the placenta and vascular endothelial cells. We performed a nested case-control study, selected from a large prospective cohort of over 2000 participants. Circulating ADM mRNA was reduced at both 28 (n = 39 vs 248 controls, p = 0.005) and 36 weeks' of pregnancy (n = 39 vs 205 controls, p < 0.0001) in those destined to develop term preeclampsia. It was also significantly reduced in the circulation of women with established early-onset preeclampsia (n = 34 vs 21 controls, p = 0.01). ADM mRNA (n = 34 vs 12 controls) and protein (n = 53 vs 17 controls) were significantly decreased in placental tissue from women with early-onset preeclampsia (p = 0.02, p = 0.0002 respectively), suggesting the placenta is a possible source of the reduced circulating mRNA. Functional studies in primary endothelial cells revealed significantly reduced ADM mRNA expression when cells were exposed to cytotrophoblast conditioned media (derived from normotensive pregnancies, p < 0.0001) or TNFα (p < 0.0001), suggesting another possible source of reduced circulating ADM mRNA is the endothelium. Circulating ADM mRNA, but not protein, is reduced 10-12 weeks before the diagnosis of term preeclampsia. It may be of endothelial or placental origin. Whole blood mRNA is a rich source of potential biomarker discovery in the prediction of preeclampsia.

Topics: Adrenomedullin; Adult; Biomarkers; Case-Control Studies; Cell-Free Nucleic Acids; Cohort Studies; Female; Humans; Pre-Eclampsia; Pregnancy; Pregnancy Trimester, Third; Prenatal Diagnosis; Prospective Studies; RNA, Messenger; Sensitivity and Specificity

Smoking in pregnancy reduces preeclampsia risk, but the mechanism of this effect is unknown. Prior studies have demonstrated that women with preeclampsia have lower placental adrenomedullin (AM) expression, and cigarette smoke extract (CSE) treatment of placental trophoblast cells in culture increases AM cellular production. We hypothesized that CSE alters trophoblast invasion through an AM-mediated mechanism, and that placental AM expression is greater among smokers. HTR-8/SVneo trophoblast cells were incubated for 24 hours in Matrigel-invasion chambers with 6 treatment groups: nonstimulated (NS), AM, AM inhibitor (AM22-52), 1% CSE, AM + AM22-52, and 1% CSE + AM22-52. Cells that penetrated the lower surface of the chambers were quantified, invasion indices were calculated, and compared using a 1-way analysis of variance with Bonferroni corrections for multiple comparisons. Trophoblast cells treated with both AM and 1% CSE demonstrated increased cellular invasion compared to NS controls (1.5-fold [P < .01] and 1.45-fold [P < .01], respectively). Cotreatment with the AM inhibitor significantly attenuated the increased invasion seen with both AM and CSE alone. Next, the placental tissue was obtained from 11 smokers and 11 nonsmokers at term and processed for immunohistochemistry (IHC) and real-time quantitative polymerase chain reaction (PCR) for AM. Placentas from smokers demonstrated more intense AM staining and increased AM gene (ADM) expression compared to placentas from nonsmokers (P = .004 for IHC, P = .022 for PCR). The CSE increases trophoblast cell invasion through an AM-mediated process, and placental AM expression is increased among term smokers compared to nonsmokers. These findings provide evidence that the AM pathway may play a role in the protection from preeclampsia seen in smokers.

Topics: Adolescent; Adrenomedullin; Adult; Case-Control Studies; Cell Line; Cell Movement; Female; Gene Expression Regulation; Hormone Antagonists; Humans; Pre-Eclampsia; Pregnancy; RNA, Messenger; Signal Transduction; Smoke; Smoking; Trophoblasts; Young Adult

Reduced maternal plasma levels of the peptide vasodilator adrenomedullin have been associated with adverse pregnancy outcomes. We measured the extent to which genetic polymorphisms in the adrenomedullin signaling pathway are associated with birth weight, glycemic regulation, and preeclampsia risk.. We genotyped 1,353 women in the Pregnancy, Infection, and Nutrition Postpartum Study for 37 ancestry-informative markers and for single-nucleotide polymorphisms in adrenomedullin (ADM), complement factor H variant (CFH), and calcitonin receptor-like receptor (CALCRL). We used linear and logistic regression to model the association between genotype and birth weight, glucose loading test (GLT) results, preeclampsia, and gestational diabetes (GDM). All models were adjusted for pregravid body mass index, maternal age, and probability of Yoruban ancestry. p values of < 0.05 were considered statistically significant.. Among Caucasian women, ADM rs57153895, a proxy for rs11042725, was associated with reduced birth weight z-score. Among African-American women, ADM rs57153895 was associated with increased birth weight z-score. Two CALCRL variants were associated with GDM risk. CFH rs1061170 was associated with higher GLT results and increased preeclampsia risk.. Consistent with studies of plasma adrenomedullin and adverse pregnancy outcomes, we found associations between variants in the adrenomedullin signaling pathway and birth weight, glycemic regulation, and preeclampsia.

Topics: Adolescent; Adrenomedullin; Adult; Birth Weight; Black or African American; Calcitonin Receptor-Like Protein; Complement Factor H; Diabetes, Gestational; Female; Genetic Predisposition to Disease; Glucose Tolerance Test; Humans; Linear Models; Logistic Models; Polymorphism, Single Nucleotide; Pre-Eclampsia; Pregnancy; Signal Transduction; White People; Young Adult

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

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

Levels of the peptide hormone adrenomedullin (AM) are elevated during normal pregnancy, but whether this differs during complications of pregnancy remains unresolved. AM can be quantified by measuring its pre-prohormone byproduct, midregional pro-adrenomedullin (MR-proADM). MR-proADM has shown prognostic value as a biomarker of heart failure, sepsis, and community-acquired pneumonia. Given the relevance of AM to pregnancy, we tested the hypothesis that MR-proADM provides a biomarker for preeclampsia. We find that MR-proADM plasma concentrations are blunted in severe preeclampsia and that MR-proADM is similarly effective as established biomarkers endoglin and placental growth factor at discriminating patients with severe preeclampsia from controls.

Topics: Adrenomedullin; Adult; Biomarkers; Case-Control Studies; Female; Humans; Pre-Eclampsia; Pregnancy; Protein Precursors; Young Adult

The remodeling of maternal uterine spiral arteries (SAs) is an essential process for ensuring low-resistance, high-capacitance blood flow to the growing fetus. Failure of SAs to remodel is causally associated with preeclampsia, a common and life-threatening complication of pregnancy that is harmful to both mother and fetus. Here, using both loss-of-function and gain-of-function genetic mouse models, we show that expression of the pregnancy-related peptide adrenomedullin (AM) by fetal trophoblast cells is necessary and sufficient to promote appropriate recruitment and activation of maternal uterine NK (uNK) cells to the placenta and ultimately facilitate remodeling of maternal SAs. Placentas that lacked either AM or its receptor exhibited reduced fetal vessel branching in the labyrinth, failed SA remodeling and reendothelialization, and markedly reduced numbers of maternal uNK cells. In contrast, overexpression of AM caused a reversal of these phenotypes with a concomitant increase in uNK cell content in vivo. Moreover, AM dose-dependently stimulated the secretion of numerous chemokines, cytokines, and MMPs from uNK cells, which in turn induced VSMC apoptosis. These data identify an essential function for fetal-derived factors in the maternal vascular adaptation to pregnancy and underscore the importance of exploring AM as a biomarker and therapeutic agent for preeclampsia.

Topics: Adrenomedullin; Animals; Apoptosis; Calcitonin Receptor-Like Protein; Chemokines; Decidua; Female; Fetus; Giant Cells; Humans; Immunity, Innate; Killer Cells, Natural; Male; Maternal-Fetal Exchange; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Mice; Mice, 129 Strain; Mice, Inbred C57BL; Mice, Knockout; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Phenotype; Placenta; Pre-Eclampsia; Pregnancy; Receptors, Adrenomedullin; Trophoblasts

We tested the hypothesis that cigarette smoke extract (CSE) leads to differences in expression of genes involved in angiogenesis and affects cell viability and migration in a first-trimester cytotrophoblast cell line (HTR-8/SVneo). HTR-8/SVneo cells were treated with 1% CSE, and gene expression for adrenomedullin (ADM), placental growth factor (PlGF), soluble fms-like tyrosine kinase 1 (sFLT-1), and vascular endothelia growth factor (VEGF) and protein content for ADM, PlGF, and sFlt-1 determined. A cell viability assay and a cell migration scratch assay were utilized following treatment with CSE with and without ADM inhibitor. Adrenomedullin, PlGF, and VEGF gene transcripts were significantly upregulated by 1% CSE treatment compared with unstimulated cells or cells treated with nicotine alone. Neither 1% CSE nor nicotine treatment alone affected sFlt-1 gene expression. There was a significant increase in secreted ADM protein from cells treated with 1% CSE detected by enzyme-linked immunosorbant assay, though no differences in PlGF or sFlt-1 production were seen. Treatment with 1% CSE increased cell viability and cell migration compared with unstimulated cells and was inhibited by co-treatment with ADM inhibitor. Treatment of a first-trimester trophoblast cell line with CSE increases cell viability and cell migration that are reversed by co-treatment with ADM inhibitor, suggesting that ADM at least partially mediates cell growth and viability following CSE treatment.

Topics: Adrenomedullin; Cell Line; Cell Movement; Cell Survival; Female; Gene Expression; Humans; Nicotiana; Nicotine; Placenta Growth Factor; Pre-Eclampsia; Pregnancy; Pregnancy Proteins; Pregnancy Trimester, First; Smoke; Trophoblasts; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-1

Adrenomedullin (ADM), a peptide with vasodilatory natriuretic and diuretic properties, is secreted in many tissues and shows multidirectional activity ADM activity may play an important role in the pathophysiology of gestational hypertension (GH) and preeclampsia (PE) by involvement in compensation of failed utero-placental unit circulation.. The aim of the study was to evaluate the association of -1984A>G ADM gene polymorphism with the development of GH and PE in maternal-fetal dyads.. The study group consisted of 46 hypertensive pregnant subjects (further divided into two subgroups: 20 pregnant women with GH and 26 women with PE). 43 healthy pregnant women constituted the control group. The study and the control groups as well as the newborns were genotyped for -1984A>G ADM gene polymorphism using PCR/RLFP procedures.. Minor--1984G allele was found to be higher in both, the GH (15.00%, OR = 3.62, p = 0.05), and the PE groups (9.62, OR = 2.18, p=ns) when compared with controls (4.65%). A tendency for higher frequency of minor -1984G allele (12.50 vs. 6.98% in controls, OR = 1.91, p=ns) was observed in the newborns from the GH group. It was also noteworthy that coexistence of both heterozygous genotypes of maternal-fetal dyads (-1984AG mother/1984AG fetus) was overrepresented in the GH group (15.00 vs. 6.98%, OR = 2.35, p=ns) and in the PE group (11.54 vs. 6.98%, OR = 1.74, p=ns) when compared to controls.. The observed tendency for overrepresentation of minor -1984G ADM allele in the GH and PE women and their newborns, despite lack of statistical significance, suggests participation of this genetic variant in the pathogenesis of the mentioned conditions. Additionally the obtained results could indicate that maternal-fetal gene-gene interaction may be a potential source of adverse perinatal outcomes.

Topics: Adrenomedullin; Adult; Female; Humans; Hypertension; Hypertension, Pregnancy-Induced; Infant, Newborn; Maternal-Fetal Exchange; Pilot Projects; Polymorphism, Genetic; Pre-Eclampsia; Pregnancy; Pregnancy Outcome; Risk Factors; Young Adult

Nowadays the possible role of vasoactive peptide adrenomedullin (ADM) is considered in the etiology of preeclampsia (PE), where ADM is indicated to be a protective factor decreasing blood pressure. The aim of this study was to evaluate the role of -1984A>G ADM gene polymorphism and its connection with ADM plasma level in women with gestational hypertension (GH) and preeclampsia.. 63 hypertensive (30 with GH and 33 with PE) and 94 healthy pregnant women were included into the study The frequency of genotypes and alleles of -1984A>G ADM gene polymorphism was examined by PCR/RFLP method. ADM concentration was measured by ELISA method.. In GH subgroup higher frequency of heterozygous AG genotype (16.67% vs. 8.50%, O.R. = 2.68, p = ns) and G allele (11.67 vs. 4.30%, O.R. = 2.97, p = 0.043) was observed. In PE subgroup overrepresentation of heterozygous AG genotype (15.15% vs. 8.5%) and slightly higher frequency of G allele (p = ns) were noted. In AA genotype subgroup of hypertensive women in comparison to the AG+GG genotype group higher proteinuria value (212.1 vs. 90.9 mg/dl, p < 0.0001), lower systolic (171.1 vs. 177.3 mmHg), as well as lower diastolic blood pressure level (107.1 vs. 111.4 mmHg) were noted. The highest ADM plasma level was observed in the group of women with PE (1.817 vs. 1.692 ng/ml, p = ns). Moreover, higher ADM plasma concentration in patients with AA genotypes in comparison to the carriers of AG and GG genotypes (1.844 vs. 1.402 ng/ml, p = ns) was noted.. Higher ADM plasma concentration in women with PE suggests possible correlation between ADM level and pathological changes in cardiovascular system during pregnancy Overrepresentation of genotypes containing at least one mutated G allele of the -1984A>G ADM gene polymorphism in women with GH and PE suggests participation of this allele in pathogenesis of these conditions. Higher ADM concentration in carriers of homozygous AA genotype found in GH and PE groups indicates the possible important role of A allele in prevention of GH/PE appearance.

Topics: Adrenomedullin; Adult; Biomarkers; Female; Gene Frequency; Genotype; Humans; Polymorphism, Genetic; Pre-Eclampsia; Pregnancy; Reproducibility of Results; Young Adult

Adrenomedullin (ADM) is indicated to be a biologically active polypeptide released by endothelium with strong hypotensive, long-acting vasodilatator properties. It is suggested that development of preeclampsia is partly related to decreased ADM influence on blood vessels.. The purpose of this study was to evaluate the adrenomedullin mRNA expression in placenta of preeclamptic women and additionally to assess the correlation between ADM mRNA expression and -1984A > G ADM gene polymorphism.. 26 preeclamptic (PE), 20 with gestational hypertension (GH) and 43 normotensive healthy pregnant women have been involved into the study. The placenta samples were collected instantly after delivery from the central part of maternal side. The ADM gene expression was measured with the real-time polymerase chain reaction (rt-PCR). The results were standardized according to the reference glyceraldehyde-3-phosphate dehydrogenase (GAPDH) gene. The -1984A > G ADM gene polymorphism was determined by PCR/RFLP assay. Lower expression of ADM mRNA in PE group (0.881 +/- 0.254 vs. 1.039 +/- 0.391 in controls, ns) has been investigated. In PE group the placental ADM mRNA expression was slightly higher at women carrying AA genotype (0.890 +/- 0.263 vs. 0.842 +/- 0.231, ns). In the control group higher placental ADM mRNA expression in women with AG + GG genotype of -1984A > G ADM gene polymorphism (1.249 +/- 0.431) in comparison to women carrying AA genotype (1.036 +/- 0.356, ns) was observed. The study also revealed negative correlation between placental ADM mRNA expression and systolic blood pressure in hypertensive pregnant women (p = 0.020).. Reduced mRNA expression for ADM in the placenta connected with reverse correlation of systolic blood pressure in preeclamptic women suggests the significant role of disturbances in placental secretion of ADM in etiology of preeclampsia.

Topics: Adrenomedullin; Adult; Biomarkers; Female; Gene Frequency; Genotype; Humans; Polymerase Chain Reaction; Polymorphism, Genetic; Pre-Eclampsia; Pregnancy; Reference Values; Reproducibility of Results; RNA, Messenger

The aim of the study was to investigate the role of malondialdehyde, nitric oxide and adrenomedullin in the etiopathogenesis of preeclampsia.. Forty-two pregnant women with preeclampsia and 30 healthy pregnant women were involved. The plasma concentrations of malondialdehyde, nitric oxide, and adrenomedullin were compared between the study group and the control group.. In women with preeclampsia the plasma concentrations of malondialdehyde was higher while nitric oxide and adrenomedullin concentrations were lower compared to control subjects.. We concluded that the plasma levels of ADM and NO are decreased while MDA levels are increased in subjects with preeclampsia and that might contribute to the pathophysiology of preeclampsia through the lack of a paracrine vasodilatory effect on uteroplacental blood flow.

Topics: Adrenomedullin; Female; Humans; Malondialdehyde; Nitric Oxide; Patient Selection; Pre-Eclampsia; Pregnancy

The aim of this study was to evaluate whether maternal circulating adrenomedullin (AM) values in patients with preeclampsia are different from those in normotensive pregnant women at different gestational ages.. In a prospective clinical study, 90 women aged 17 to 40 years old, were divided into 4 main groups: group I (45 women): Normotensive pregnant women at first trimester (15 women), second trimester (15 women), and third trimester (15 women) of pregnancies. Group II (15 women): Pregnant women with preeclampsia at 25 to 38 weeks of gestation. Group III (15 women): Normotensive healthy nonpregnant women. Group IV (15 women): Hypertensive nonpregnant women. The plasma AM concentration was measured in all women by using enzyme immunoassay kits.. Plasma AM levels in pregnant women with normal blood pressure at different gestational ages (first, second, and third trimesters) were statistically significantly higher than those detected in nonpregnant normotensive women and significantly increased with increasing gestational age (P < .001). Moreover, there was significant positive correlation between plasma AM levels and increasing gestational age (r = 0.915, P < .001). Preeclamptic patients had the highest mean plasma AM levels compared with all other groups, which is statistically significant (P < .001) and there was a significant positive correlation between plasma AM levels and systolic blood pressure, diastolic blood pressure, severity of preeclampsia, and proteinuria in pregnant patients with preeclampsia.. Maternal plasma AM concentration increases throughout pregnancy and increases as gestational age progresses. AM production starts very early in gestation, suggesting that it may have an important role in human reproduction, from implantation to delivery. Maternal plasma AM level in preeclampsia appears to be higher than that in normal pregnancy.

Topics: Adolescent; Adrenomedullin; Adult; Biomarkers; Egypt; Female; Humans; Pre-Eclampsia; Pregnancy; Reproducibility of Results; Sensitivity and Specificity

The relationship between Pre-eclampsia (PE) and placental production of Adrenomedullin (AdM) is not completely understood. This study measured placental and fetal membrane AdM protein concentrations by specific radioimmunoassay and mRNA expression by Northern blot analysis in samples obtained at either term or preterm gestation from women either in labour or not in labour. Samples were obtained from women with normotensive and pre-eclamptic pregnancies. There were significant increases in immunoreactive AdM protein concentration (pg/mg DNA) in choriodecidua and amnion of women with PE compared to normal pregnancy for the preterm not-in-labour group (choriodecidua: control 124 +/- 16, n = 10, PE 361 +/- 35, n = 10; amnion: control 94 +/- 12, n = 10, PE 153 +/- 19, n = 10) and for the term not-in-labour (choriodecidua: control 128 +/- 17, n = 14, PE 459 +/- 51, n = 8; amnion: control 112 +/- 15, n = 14, PE 253 +/- 57, n = 8) and in-labour (choriodecidua: control 531 +/- 74, n = 14, PE 881 +/- 188, n = 8; amnion: control 545 +/- 84, n = 14, PE 1008 +/- 230, n = 8) groups. AdM mRNA relative abundance was greater in preterm, not-in-labour choriodecidual samples in PE, but not in amnion. In addition, this study observed labour-associated increases in choriodecidual and amniotic irAdM in term pre-eclamptic and control patients. However, there were no significant changes in AdM protein or mRNA expressions between any of the groups for placental tissue. These results suggest that fetal membranes, but not placental, production of AdM is increased at the post-translational level during PE in preterm and term tissues and at the pre-translational level during PE in preterm tissues. Fetal membranes, AdM may play an important role in the regulation of feto-placental hemodynamics and fetal physiology during pre-eclampsia.

Topics: Adrenomedullin; Amnion; Blotting, Northern; Chorion; Extraembryonic Membranes; Female; Humans; Peptides; Placenta; Pre-Eclampsia; Pregnancy; RNA, Messenger

To investigate the differential expression of adrenomedullin (ADM) in the placentas of women with normal and preeclamptic pregnancies, and explore the importance of ADM and its signal pathway in the development of preeclampsia.. Ten pregnant women complicated with preeclampsia during the late term(>or=35 wk) were selected for this study along with 7 normal control pregnant women (>or=39 wk). The total RNA was extracted and sections of fresh placental tissues were prepared, and ADM expressions at mRNA and protein levels in women with normal and preeclamptic pregnancies were determined by Northern blotting and immunohistochemistry, respectively.. At both mRNA and protein levels, the expression of ADM in the placentas of preeclamptic women was significantly reduced obviously as compared with that of the normal control (P<0.05), suggesting that ADM expression reduction in preeclamptic placenta might be associated with the development of preeclampsia.

Topics: Adrenomedullin; Adult; Blotting, Northern; Female; Gene Expression Profiling; Humans; Immunohistochemistry; Placenta; Pre-Eclampsia; Pregnancy; RNA, Messenger

To observe the adrenomedullin (AM) and total nitrite levels in the milk of preeclamptic and normal pregnant women.. Fifteen women with preeclampsia and 15 normal pregnant women were included in the study. Total nitrite was quantitated by Griess reaction, while AM was measured by HPLC.. The levels of AM and total nitrite in colostrum and 30th-day breast milk were decreased in preeclamptics. Total nitrite levels (micromol/l) were 56.09 +/- 11.18 vs. 82.20 +/- 12.01, P < 0.05, in colostrum of preeclamptics and controls, respectively. The level of total nitrite was 37.75 +/- 12.10 vs. 53.28 +/- 10.25, P < 0.05, in 30th-day milk of same patients. AM levels (pg/ml) were 11.18 +/- 1.11 vs. 16.59 +/- 1.24, P < 0.0001, in colostrum of preeclamptics and controls, respectively. In 30th-day milk of same patients, AM levels were 8.41 +/- 1.39 vs. 12.18 +/- 1.48, P < 0.005, respectively.. This report shows for the first time that human milk has decreased levels of AM and total nitrite in preeclampsia.

Topics: Adrenomedullin; Female; Humans; Milk, Human; Nitrites; Peptides; Pre-Eclampsia; Pregnancy; Turkey

We hypothesize that administration of adrenomedullin (AM), an endogenous vasodilator, will ameliorate the hypertension and growth restriction associated with chronic nitric oxide inhibition induced by L-omega nitro-L-arginine methyl ester (L-NAME) infusion in pregnant rats.. Osmotic minipumps were inserted on day 14 of gestation to deliver continuously either AM, L-NAME, AM+L-NAME, or vehicle control. Systolic blood pressure was recorded daily in pregnant rats. Pregnant rats were either sacrificed on gestational days 15, 16, 17, 18, or 22, or they were allowed to deliver at term. The placentas from all of the treated groups were fixed for 24 hr in Bouin solution, sectioned, processed, embedded in paraffin, and stained with hematoxylin and eosin. The placentas were graded for the quality of fetal vessel development in the labyrinth.. Systolic blood pressure was increased in AM+L-NAME-treated rats. The animals that delivered in the AM+L-NAME group exhibited decreased pup weight (L-NAME and AM+L-NAME, 5.2+/-0.1 compared with 6.4+/-0.1 g for both AM and controls, p<0.001) and increased pup mortality (AM+L-NAME, 44.4% compared with 16.7% in L-NAME, 0% in AM and 3.1% in controls, p<0.001 AM+L-NAME compared with controls). Increased decidual necrosis, necrosis in the labyrinth, and deficient fetal vessel development in the labyrinth was identified in the placentas treated with AM+L-NAME.. Addition of the endogenous vasodilator AM to an L-NAME-induced state of chronic NO inhibition did not ameliorate hypertension and growth restriction.

Topics: Adrenomedullin; Animals; Blood Pressure; Disease Models, Animal; Dose-Response Relationship, Drug; Enzyme Inhibitors; Female; Fetal Growth Retardation; Fetal Weight; Infusions, Intravenous; Litter Size; NG-Nitroarginine Methyl Ester; Nitric Oxide; Peptides; Placenta; Pre-Eclampsia; Pregnancy; Rats; Rats, Sprague-Dawley; Systole; Vasodilator Agents

To explore the mechanisms of adrenomedullin (ADM) regulation in normal and preeclamptic (PE) states, we determined placental production of ADM and ADM regulation by cytokines. Isolated, purified cytotrophoblast cultures from normal (n=8) and PE (n=10) placentas were cultured for 3 days in the absence or presence of 10 ng/mL epidermal growth factor (EGF), 1 ng/mL transforming growth factor (TGF)-beta1, 10 ng/mL tumor necrosis factor (TNF)-alpha, or 100 U/mL interferon (IFN)-gamma. Cells were also cultured for 3 days in 10% fetal bovine serum for determination of syncytial formation by desmoplakin staining. Pieces of normal and PE placentas were snap-frozen for ADM mRNA measurement. Results showed that basal ADM production into culture medium by radioimmunoassay was significantly lower in PE placental cells. EGF significantly stimulated ADM production in normal trophoblasts but did not in PE placentas. None of the factors TNF-alpha, TGF-beta1, or IFN-gamma altered ADM secretion in either normal or PE placentas. ADM expression by Northern blot analysis demonstrated a 34.3+/-8.3% reduction in mRNA expression in PE placentas. Syncytialization, as assessed by desmoplakin-outlined syncytial units, was decreased in PE placentas (day 3: normal, 16.7+/-1.3%; PE, 5.5+/-2.0%; P<0.01, ANOVA). However, there was a normal increment in syncytialization in response to EGF in normal and PE trophoblast preparations (EGF day 3: normal, 43.8+/-5.6%; PE, 46.1+/-12.3%). We conclude that spontaneous placental syncytialization is impaired in PE and that ADM production is markedly reduced in PE, possibly owing to an impaired EGF response. These abnormalities indicate poor placental production of ADM as the likely cause of a failed compensatory increase in maternal serum ADM levels in PE.

Topics: Adrenomedullin; Cells, Cultured; Epidermal Growth Factor; Female; Giant Cells; Humans; Peptides; Pre-Eclampsia; Pregnancy; RNA, Messenger; Trophoblasts

In pathological pregnancies, alterations in circulating maternal and fetal adrenomedullin (ADM) concentrations may mediate compensatory vascular responses in the fetal or placental circulation. To address whether ADM is a potential paracrine vasoactive factor within the placenta, the regional distribution and cellular localization of ADM mRNA expression were determined by Northern blot and in situ hybridization of different regions of the placenta and fetal membranes from pregnancies complicated by severe preeclampsia [<28 wk (n = 7) and >28 wk (n = 13)] and from normotensive pregnancies [<28 wk (n = 6) and >28 wk (n = 15)]. Northern blotting revealed that ADM mRNA (1.3 kb) was expressed in chorionic villi and basal plate regions, but was most abundantly expressed in the choriodecidua. By in situ hybridization, ADM mRNA was localized to the syncytiotrophoblasts and the extravillous cytotrophoblasts in the basal plate and choriodecidua regions. ADM mRNA expression was increased in the choriodecidua, syncytial knots, and cytotrophoblasts in peri-infarct regions in preeclampsia. In chorionic villous explant studies maintained at reduced oxygen tension, ADM mRNA abundance was increased at 12, 24, and 48 h. ADM mRNA expressed in syncytiotrophoblasts and cytotrophoblasts in the basal plate decidua and choriodecidua may contribute to the maternal and fetal plasma levels. In preeclampsia, regional increases in ADM mRNA may be induced by hypoxia and mediate local fetal/placental adaptive responses to reduced placental perfusion.

Topics: Adrenomedullin; Blotting, Northern; Case-Control Studies; Chorion; Chorionic Villi; Decidua; Female; Humans; In Situ Hybridization; Peptides; Placenta; Pre-Eclampsia; Pregnancy; RNA, Messenger; Time Factors; Tissue Distribution; Trophoblasts

In this study, we used the animal model of preeclampsia. The blood pressure in animals receiving L-NAME at 25 mg/day were significantly higher compared to that of rats receiving saline solution only. In addition, L-NAME treated rats showed a high fetal mortality as compared with intact rats. Also, we demonstrated infusion of AM reverse the hypertension and decrease in pup mortality induced by L-NAME during pregnancy. We showed that the AM mRNA levels predominantly exists in a high level in the placenta, uterus and ovary as compared with other tissues. These evidences suggest that AM may have a possible important role during pregnancy. In conclusion, the present study suggest that L-NAME-induced elevated blood pressure and increased fetal mortality can be reversed by low dose of AM. Thus AM may play an important role in the regulation of blood pressure, the blood supply to the utero-placental unit and fetal development.

Topics: Adrenomedullin; Animals; Blood Pressure; Disease Models, Animal; Female; Genitalia, Female; Peptides; Placental Circulation; Pre-Eclampsia; Pregnancy; Rats; Rats, Wistar; RNA, Messenger

The human placenta expresses a variety of vasoactive substances and neuropeptides, which play an important role in the regulation of placental blood flow in both the maternal and foetal compartment and are therefore of critical importance for foetal growth and development. Our study was planned to examine placental mRNA amounts of vasodilatory adrenomedullin (AM), calcitonin gene-related peptide (CGRP) and their receptors (AM-R and CGRP-R) in preeclampsia and HELLP syndrome (hemolysis, elevated liver enzymes, low platelets). These are severe maternal conditions leading to an altered uteroplacental and fetoplacental perfusion and a higher risk for foetal growth retardation, premature delivery, infant mortality, and even maternal death.. We included 17 patients with preeclampsia, four women with HELLP syndrome and 34 controls. After delivery, the mRNA levels of AM, AM-R, CGRP, CGRP-R, glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and -actin were measured in placental villi and chorionic plates using quantitative real-time PCR.. AM/-actin and AM/GAPDH mRNA ratios were significantly lower in placental villi in preeclampsia than in controls (P<0.05) as were CGRP/-actin and CGRP/GAPDH mRNA ratios in chorionic plates (P<0.05). Placental AM-R and CGRP-R mRNA amounts were unaffected.. Our data show a reduction of AM and CGRP mRNAs in contrast to unchanged mRNA levels of their receptors in placenta specimens of women with preeclampsia or HELLP syndrome.

Topics: Actins; Adrenomedullin; Adult; Calcitonin Gene-Related Peptide; Female; Gene Expression; Glyceraldehyde-3-Phosphate Dehydrogenases; HELLP Syndrome; Humans; Peptides; Placenta; Polymerase Chain Reaction; Pre-Eclampsia; Pregnancy; Receptors, Adrenomedullin; Receptors, Calcitonin Gene-Related Peptide; Receptors, Peptide; Regression Analysis; RNA, Messenger

Adrenomedullin is a potent vasodilatory peptide with plasma levels that increase during pregnancy. Although fetoplacental adrenomedullin levels are reported to increase in preeclampsia, maternal plasma levels may be elevated or decreased, or they may resemble those in normal pregnancy. In other hypertensive conditions, adrenomedullin increases. Therefore, we hypothesized that maternal plasma adrenomedullin levels would be higher in hypertensive pregnancies than in normotensive pregnancies and that the higher placental resistance found in preeclamptic pregnancies results from blunted activity of adrenomedullin on the vasculature. Adrenomedullin concentrations in plasma from women with normotensive pregnancies, gestational hypertension, and preeclampsia were determined by radioimmunoassay. Stem villous arteries from normotensive and preeclamptic pregnancies were dissected and mounted on a wire myograph system. Arteries were first preconstricted to 80% of their maximum constriction with U46619, a thromboxane A(2) mimetic, and exposed to cumulative doses of adrenomedullin (1x10(-)(9) to 3x10(-)(7) mol/L). Contrary to our hypothesis, there were no significant differences in maternal plasma adrenomedullin levels among patients with normal pregnancies, gestational hypertension, and preeclampsia. Adrenomedullin significantly relaxed arteries from both normal and preeclamptic placentas, but there was no significant difference between the 2 groups. During normal pregnancy, adrenomedullin may contribute to the low placental vascular resistance. This pathway appears to be intact in preeclampsia. We conclude that the increased placental vascular resistance observed in preeclampsia is due neither to reduced adrenomedullin secretion nor to an attenuated vascular responsiveness. Moreover, unlike other hypertensive disorders, there is no compensatory rise in circulating adrenomedullin levels.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Adrenomedullin; Adult; Arteries; Dose-Response Relationship, Drug; Female; Humans; In Vitro Techniques; Peptides; Placenta; Potassium Chloride; Pre-Eclampsia; Pregnancy; Vasoconstrictor Agents; Vasodilation

The purpose of the present study was to investigate whether placental immunohistochemical adrenomedullin expression in normal normotensive pregnancies is different from that in pregnancies with pre-eclampsia. Placental tissues were obtained from seven normal normotensive pregnancies and 12 pregnancies with pre-eclampsia. The intensity of adrenomedullin staining in syncytiotrophoblasts was evaluated by means of immunohistochemistry and the ratio of the number of intact tertiary villi to that of total tertiary villi (intact/total villi ratio) was determined. The intensity of adrenomedullin expression in the placenta obtained from pregnancies with pre-eclampsia was significantly decreased compared with expression in placentas from uncomplicated normotensive pregnancies (P < 0.005). The intact/total villi ratio in placentas obtained from pregnancies with pre-eclampsia was significantly lower than that in placentas from normal normotensive pregnancies (P < 0.0001). In the amnion and extravillous trophoblast cells in both groups, no difference for the intensity of adrenomedullin expression was noted. These results suggest that adrenomedullin synthesis in the villous syncytiotrophoblasts is decreased in pregnancies with pre-eclampsia.

Topics: Adrenomedullin; Adult; Amnion; Antihypertensive Agents; Birth Weight; Female; Gestational Age; Humans; Immunoenzyme Techniques; Organ Size; Peptides; Placenta; Pre-Eclampsia; Pregnancy

We examined the effect of adrenomedullin on the cardiovascular system of an animal model for preeclampsia. An inhibitor of nitric oxide synthase, N(G)-nitro-L-arginine methyl ester (L-NAME), was infused subcutaneously into rats at a constant rate from day 14 of pregnancy to make an animal model for preeclampsia. Adrenomedullin was continuously infused intravenously at a dose of 3 or 10 pmol/h from day 17 of pregnancy. The basal systolic blood pressure was significantly higher in the L-NAME treated rats than in the control rats. The adrenomedullin administration at day 19 of pregnancy showed a significant decrease in the blood pressure in the L-NAME treated rats than in vehicle rats during infusion. The blood pressure of normal pregnant rats did not significantly decrease by adrenomedullin infusion. The adrenomedullin decreased pup mortality of the L-NAME treated rats. Adrenomedullin attenuated the L-NAME induced hypertension and pup mortality. On the other hand, adrenomedullin administration in both pregnant rats in early gestation (5-11 days of pregnancy) and in non-pregnant rats did not show any significant effect on L-NAME-induced hypertension. The adrenomedullin mRNA level was predominantly expressed at high levels in the ovary, uterus and placenta, but at low levels in other tissues in pregnant rats in late gestation. The adrenomedullin mRNA level of the L-NAME treated rats in placenta decreased more than in the normal pregnant rats in late gestation (P < 0.05). These findings suggest that the adrenomedullin might play an important role in the regulation of the cardiovascular system of the mother and fetoplacental unit in rats.

Topics: Adrenomedullin; Animals; Antihypertensive Agents; Blood Pressure; Blotting, Northern; Body Weight; Disease Models, Animal; Enzyme Inhibitors; Female; Fetus; Hypertension; Infusions, Intravenous; NG-Nitroarginine Methyl Ester; Peptides; Pre-Eclampsia; Pregnancy; Pregnancy, Animal; Rats; Rats, Wistar; RNA, Messenger; Time Factors

Adrenomedullin (AM) is a peptide that elicits a long-lasting vasorelaxant activity, while atrial natriuretic peptide (ANP) has also been shown to be a potent vasodilatory agent. To clarify the possible role of AM and ANP in the physiology of pregnancy and pathophysiology of pre-eclampsia, we measured plasma concentrations of these peptides in non-pregnant women, normal pregnant women and women with pre-eclampsia. A gradual increase in plasma AM was observed as pregnancy progressed. The plasma AM concentrations during the second trimester (12.7 +/- 1.4 fmol/ml) were significantly elevated, in comparison with the non-pregnant follicular phase (6.4 +/- 0.61 fmol/ml), luteal phase (6.0 +/- 0.49 fmol/ml), and the first trimester (6.5 +/- 0.8 fmol/ml). The plasma AM concentrations of the third trimester (21.5 +/- 1.4 fmol/ml) were significantly elevated when compared with those of the second trimester (P < 0.05). Northern blot analysis confirmed the expression of the AM mRNA transcript (1.6 kb) in third trimester placentas. In comparison with those observed at term (25.3 +/- 4.5 fmol/ml), the plasma concentrations were significantly reduced post-partum (6.4 +/- 0.6 fmol/ml). In the third trimester, plasma AM concentrations did not differ significantly between women with pre-eclampsia (17.2 +/- 2.3 fmol/ml) and normal pregnant women. In contrast, the plasma ANP concentrations in pre-eclampsia (39.5 +/- 7. 1 pg/ml) were significantly elevated when compared with those of the normal third trimester (14.4 +/- 1.4 pg/ml) (P < 0.05). ANP concentrations were reasonably constant throughout the pregnancy.

Topics: Adrenomedullin; Atrial Natriuretic Factor; Female; Follicular Phase; Gene Expression; Humans; Luteal Phase; Peptides; Placenta; Postpartum Period; Pre-Eclampsia; Pregnancy; Pregnancy Trimester, First; Pregnancy Trimester, Second; Pregnancy Trimester, Third; RNA, Messenger

To investigate the relationship between adrenomedullin(ADM) and pregnancy induced hypertension(PIH).. The ADM values in the plasma from 12 normal term-pregnant women and 26 women with PIH were determined by specific radioimmunoassay.. (1) The ADM value in the PIH (24.67 +/- 1.27) ng/L increased significantly than that of normal pregnancy (19.16 +/- 1.17) ng/L (P < 0.05). (2) There were significant difference between severe(30.00 +/- 1.17) ng/L moderate (24.80 +/- 0.70) ng/L and mild (19.38 +/- 2.65) ng/L PIH groups (P < 0.001). (3) Significant positive correlation was found between plasma ADM value and mean arterial pressure (r = 0.775, P < 0.001).. The ADM level is closely associated with PIH and may plan an important role in PIH.

Topics: Adrenomedullin; Adult; Antihypertensive Agents; Female; Humans; Peptides; Pre-Eclampsia; Pregnancy; Vasodilator Agents

Topics: Adrenomedullin; Female; Humans; Peptides; Pre-Eclampsia; Pregnancy

Adrenomedullin is a novel peptide that elicits a long-lasting vasorelaxant activity. Recently, we found high concentrations of adrenomedullin in maternal and umbilical cord plasma and in amniotic fluid in full-term human pregnancy, indicating a role of this peptide during gestation. To investigate the possibility that adrenomedullin is involved in the pathophysiology of preeclampsia, we measured its concentration in maternal and fetoplacental compartments. We studied 12 normotensive nonpregnant women, 13 hypertensive nonpregnant subjects, 29 patients with preeclampsia, and 30 normotensive pregnant women. In all patients, plasma was collected from the cubital vein, and amniotic fluid samples were obtained by transabdominal amniocentesis or at elective cesarean section. Plasma samples from umbilical vein and placental tissues were collected at delivery. Adrenomedullin was assayed on plasma and amniotic fluid samples using a specific radioimmunoassay, and its localization and distribution on placental sections was determined by immunohistochemistry. Adrenomedullin concentrations were higher in hypertensive than in normotensive nonpregnant patients. Pregnant women had higher adrenomedullin levels than nonpregnant subjects, although maternal plasma adrenomedullin concentrations did not differ between normal pregnant and preeclamptic women. Preeclamptic patients showed higher concentrations (P<0.01) than normotensive pregnant women of adrenomedullin in amniotic fluid (252+/-29 versus 112+/-10 fmol/ micromol creatinine) and umbilical vein plasma (18.1+/-2.1 versus 8. 5+/-1.1 fmol/mL). Increased local production of adrenomedullin is associated with preeclampsia. The fetus seems to be responsible for the higher levels of this hormone. Increased adrenomedullin concentrations may be necessary to maintain placental vascular resistance and/or fetal circulation at a physiological level.

Topics: Adrenomedullin; Adult; Amniotic Fluid; Case-Control Studies; Female; Fetal Blood; Humans; Peptides; Placenta; Pre-Eclampsia; Pregnancy; Radioimmunoassay; Vasodilator Agents