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Circulating and placental endoglin concentrations in pregnancies complicated by intrauterine growth restriction and preeclampsia.

ABSTRACT: Inadequate trophoblast invasion and spiral artery remodeling leading to poor placental perfusion and hypoxia are believed to underlie preeclampsia (PE) and intrauterine growth restriction (IUGR). Recent studies implicate increased circulating endoglin as a contributor to the pathogenesis of PE. The objective of this study was to determine whether placental and circulating endoglin concentrations are altered in pregnancies complicated by intrauterine growth restricted (IUGR) infants and to address the role of hypoxia on the regulation of placental endoglin. We analyzed 10 placentas each from normal pregnant (NP), PE, and IUGR subjects. Endoglin levels were 2.5-fold higher in preeclamptic placentas compared to NP (15.4+/-2.6 versus 5.7+/-1.0, p<0.01). In contrast, endoglin levels were similar in NP and IUGR placentas (5.7+/-1.0 vs 5.9+/-1.1, p=NS). Placentas from pregnancies with both PE and IUGR exhibited endoglin levels comparable to the PE group and significantly different from normotensive pregnancies with and without IUGR pregnancies (mean 14.9+/-4.0, n=9, p=0.013). Soluble endoglin concentrations in maternal plasma were comparable in NP and IUGR, but higher in women with PE (n=10 per group, p<0.05). Despite a 2-fold increase in hypoxia inducible factor, HIF-1alpha, we did not observe endoglin upregulation in NP, PE, or IUGR placental villous explants exposed to hypoxia (2% oxygen). In contrast to PE, placental or circulating endoglin is not increased in normotensive women delivering small, asymmetrically grown (IUGR) infants at term. The placentas of women with IUGR appear to be fundamentally different from PE women with respect to endoglin, despite the proposed common pathology of deficient trophoblast invasion/spiral artery remodeling and poor placental perfusion.

SUBMITTER: Jeyabalan A

PROVIDER: S-EPMC2467513 | biostudies-literature | 2008 Jun

REPOSITORIES: biostudies-literature

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Circulating and placental endoglin concentrations in pregnancies complicated by intrauterine growth restriction and preeclampsia.

Jeyabalan A A McGonigal S S Gilmour C C Hubel C A CA Rajakumar A A

Placenta 20080506 6

Inadequate trophoblast invasion and spiral artery remodeling leading to poor placental perfusion and hypoxia are believed to underlie preeclampsia (PE) and intrauterine growth restriction (IUGR). Recent studies implicate increased circulating endoglin as a contributor to the pathogenesis of PE. The objective of this study was to determine whether placental and circulating endoglin concentrations are altered in pregnancies complicated by intrauterine growth restricted (IUGR) infants and to addres ...[more]

PMID: 18462791

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Project description:Preeclampsia is one of the most severe gestational complications which is one of the leading causes of maternal and perinatal morbidity and mortality. A growth in the incidence of severe and combined forms of the pathology has been observed in recent years. According to modern concepts, inadequate cytotrophoblast invasion into the spiral arteries of the uterus and development of the ischemia-reperfusion syndrome in the placental tissue play the leading role in the development of preeclampsia, which is characterized by multipleorgan failure. In this regard, our work was aimed at studying the patterns of placental tissue transcriptome that are specific to females with PE and with physiological pregnancy, as well as identifying the potential promising biomarkers and molecular mechanisms of this pathology. We have identified 63 genes whose expression proved to differ significantly in the placental tissue of females with PE and with physiological pregnancy. A cluster of differentially expressed genes (DEG) whose expression level is increased in patients with preeclampsia includes not only the known candidate genes that have been identified in many other genome-wide studies (e.g., LEP, BHLHB2, SIGLEC6, RDH13, BCL6), but also new genes (ANKRD37, SYDE1, CYBA, ITGB2, etc.), which can be considered as new biological markers of preeclampsia and are of further interest. The results of a functional annotation of DEG show that the development of preeclampsia may be related to a stress response, immune processes, the regulation of cell-cell interactions, intracellular signaling cascades, etc. In addition, the features of the differential gene expression depending on preeclampsia severity were revealed. We have found evidence of the important role of the molecular mechanisms responsible for the failure of immunological tolerance and initiation of the pro-inflammatory cascade in the development of severe preeclampsia. The results obtained elaborate the concept of the pathophysiology of preeclampsia and contain the information necessary to work out measures for targeted therapy of this disease. ;

Project description:BackgroundCurrent methods fail to accurately predict women at greatest risk of developing fetal growth restriction (FGR) or related adverse outcomes, including stillbirth. Sexual dimorphism in these adverse pregnancy outcomes is well documented as are sex-specific differences in gene and protein expression in the placenta. Circulating maternal serum microRNAs (miRNAs) offer potential as biomarkers that may also be informative of underlying pathology. We hypothesised that FGR would be associated with an altered miRNA profile and would differ depending on fetal sex.MethodsmiRNA expression profiles were assessed in maternal serum (> 36 weeks' gestation) from women delivering a severely FGR infant (defined as an individualised birthweight centile (IBC) < 3rd) and matched control participants (AGA; IBC = 20-80th), using miRNA arrays. qPCR was performed using specific miRNA primers in an expanded cohort of patients with IBC < 5th (n = 15 males, n = 16 females/group). Maternal serum human placental lactogen (hPL) was used as a proxy to determine if serum miRNAs were related to placental dysfunction. In silico analyses were performed to predict the potential functions of altered miRNAs.ResultsInitial analyses revealed 11 miRNAs were altered in maternal serum from FGR pregnancies. In silico analyses revealed all 11 altered miRNAs were located in a network of genes that regulate placental function. Subsequent analysis demonstrated four miRNAs showed sexually dimorphic patterns. miR-28-5p was reduced in FGR pregnancies (p < 0.01) only when there was a female offspring and miR-301a-3p was only reduced in FGR pregnancies with a male fetus (p < 0.05). miR-454-3p was decreased in FGR pregnancies (p < 0.05) regardless of fetal sex but was only positively correlated to hPL when the fetus was female. Conversely, miR-29c-3p was correlated to maternal hPL only when the fetus was male. Target genes for sexually dimorphic miRNAs reveal potential functional roles in the placenta including angiogenesis, placental growth, nutrient transport and apoptosis.ConclusionsThese studies have identified sexually dimorphic patterns for miRNAs in maternal serum in FGR. These miRNAs may have potential as non-invasive biomarkers for FGR and associated placental dysfunction. Further studies to determine if these miRNAs have potential functional roles in the placenta may provide greater understanding of the pathogenesis of placental dysfunction and the differing susceptibility of male and female fetuses to adverse in utero conditions.

Project description:IntroductionThe pathophysiology of preeclampsia is largely unknown. Serum placental induced growth factor (PlGF) levels are decreased during second trimester pregnancy. Aberrant DNA methylation is suggested to be involved in the etiology of preeclampsia (PE). We hypothesize that DNA methylation is altered in PE placentas determined the methylation index by measuring placental S-adenosylmethionine (SAM) and S-adenosylhomocysteine (SAH) levels. In addition, we assessed global DNA methylation status by long-interspersed nuclear element-1 (LINE-1) and DNA methylation status of the PlGF gene.MethodsPlacental tissue of 11 early onset PE (EOPE), 11 late onset PE (LOPE) and 60 controls consisting of 25 uncomplicated controls 20 fetal growth restriction (FGR) and 15 preterm births (PTB) controls was collected from a nested case-control study of The Rotterdam Periconceptional Cohort. RNA and DNA was isolated from placental tissue and DNA was treated with sodium bisulfite. SAM and SAH levels were measured by LC-ESI-MS/MS. Methylation of LINE-1 and PlGF genes was analyzed by Sequenom Epityper and. mRNA expression of PlGF was assessed with qPCR. Differences were assessed by analysis of covariance (ANCOVA) corrected for gestational age and birth weight.ResultsPlacental SAM levels were significantly lower in placental tissue of EOPE pregnancies compared to PTB controls (mean difference -240 ± 71.4 nmol/g protein, P = 0.01). PlGF DNA methylation was decreased in placental tissue of EOPE cases versus LOPE (mean difference -17.4 ± 5.1%, P = 0.01), uncomplicated controls (mean difference -23.4 ± 5.4%%, P <0.001), FGR controls (mean difference -17.9 ± 4.6%, P = 0.002) and PTB controls (mean difference -11.3 ± 3.8% P = 0.04). No significant differences were observed in SAH, SAM:SAH ratio, LINE-1 DNA methylation and PlGF mRNA expression between groups.DiscussionThe hypomethylation state of the placenta in EOPE, which is reflected by lower SAM and PlGF DNA hypomethylation underlines the possible role of placental DNA hypomethylation in the pathophysiology of EOPE, which needs further investigation.

Dataset Information

Circulating and placental endoglin concentrations in pregnancies complicated by intrauterine growth restriction and preeclampsia.

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Circulating and placental endoglin concentrations in pregnancies complicated by intrauterine growth restriction and preeclampsia.

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