Sexual Dimorphism of Preeclampsia-Dysregulated Transcriptomic Profiles and Endothelial Function in Fetal Endothelial Cells
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE116428 | GEO | 2019/07/02
REPOSITORIES: GEO
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Project description:Introduction. Preeclampsia (PE) carries increased risks of cardiovascular- and metabolic diseases in mothers and offspring during the life course. While the severe early-onset PE (EOPE) phenotype originates from impaired placentation in early pregnancy, late-onset PE (LOPE) is in particular associated with pre-existing maternal cardiovascular- and metabolic risk factors. We hypothesize that PE is associated with altered epigenetic programming of placental and fetal tissues and that these epigenetic changes might elucidate the increased cardiovascular- and metabolic disease susceptibility in PE offspring. Methods. A nested case-control study was conducted in The Rotterdam Periconceptional Cohort comprising 13 EOPE, 16 LOPE, and three control groups of 36 uncomplicated pregnancies, 27 normotensive fetal growth restricted (FGR) and 20 normotensive preterm birth (PTB) complicated pregnancies. Placental tissue, newborn umbilical cord blood leucocytes (UC-WBC) and umbilical vein endothelial cells (HUVEC) were collected and DNA methylation of cytosine-guanine dinucleotides was measured by the Illumina HumanMethylation450K BeadChip. An epigenome-wide analysis was performed by using multiple linear regression models. Results. Epigenome-wide tissue-specific analysis between EOPE and PTB controls revealed 5001 mostly hypermethylated differentially methylated positions (DMPs) in UC-WBC and 869 mostly hypomethylated DMPs in placental tissue, situated in or close to genes associated with cardiovascular-metabolic developmental pathways. Discussion. This study shows differential methylation in UC-WBC and placental tissue in EOPE as compared to PTB, identifying DMPs that are associated with cardiovascular system pathways. Future studies should examine these loci and pathways in more detail to elucidate the associations between prenatal PE exposure and the cardiovascular disease risk in offspring.
2017-09-06 | GSE103253 | GEO
Project description:Preeclampsia (PE) has been associated with placental dysfunction, resulting in foetal hypoxia, accelerated erythropoiesis and increased erythroblast count in the umbilical cord blood (UCB). Although the detailed effects remain unknown, placental dysfunction can also cause inflammation, nutritional and oxidative stress in the fetus that can affect erythropoiesis. Here, we compared the expression of surface adhesion molecules and erythroid differentiation capacity of UCB hematopoietic stem/ progenitor cells (HSPCs), UCB erythroid profiles along with transcriptome and proteome of these cells between male and female foetuses from PE and normotensive pregnancies. While no significant differences were observed in UCB HSPC migration/ homing and in vitro erythroid colony differentiation, the UCB HSPC transcriptome and the proteomic profile of the in vitro differentiated erythroid cells differed between PE vs normotensive samples. Accordingly, despite absence of significant differences in the UCB erythroid populations in male or female foetuses from PE or normotensive pregnancies, transcriptional changes were observed during erythropoiesis, particularly affecting male foetuses. Pathway analysis suggested deregulation in mTORC1/AMPK signaling pathways controlling cell cycle, differentiation and protein synthesis. These results associate PE with transcriptional and proteomic changes in foetal HSPCs and erythroid cells that may underlie the higher erythroblast count in the UCB in PE.
2019-06-20 | PXD010364 | Pride
Project description:Endoglin is a membrane glycoprotein primarily expressed by the vascular endothelium and involved in cardiovascular diseases. Upon the proteolytic processing of the membrane-bound protein, a circulating form of endoglin (soluble endoglin, sEng) can be released, and high levels of sEng have been observed in several endothelial-related pathological conditions, where it appears to contribute to endothelial dysfunction. Preeclampsia is a multisystem disorder of high prevalence in pregnant women characterized by the onset of high blood pressure and often associated with increased levels of sEng. Although a pathogenic role for sEng involving hypertension has been reported in several animal models of preeclampsia, the exact molecular mechanisms implicated remain to be identified. To search for sEng-induced mediators, we have analyzed the protein secretome of human endothelial cells in the presence of sEng. We find that sEng induces the expression of BMP4 in endothelial cells, as evidenced by their proteomic signature, gene transcript levels and BMP4 promoter activity. A mouse model of preeclampsia with high sEng plasma levels (sEng+) showed increased levels of BMP4 transcripts in lungs and increased circulating BMP4, compared to those of control animals. In addition, after crossing female wild type with male sEng+ mice, hypertension appears 18 days after mating, precisely coinciding with the appearance of high plasma levels of BMP4. Also, serum levels of sEng and BMP4 are positively correlated in pregnant women with and without preeclampsia. Interestingly, sEng-induced arterial pressure elevation in sEng+ mice was abolished in the presence of the BMP4 inhibitor noggin, suggesting that BMP4 is a downstream mediator of sEng. These results provide a better understanding on the role of sEng in the pathobiology of preeclampsia and other cardiovascular diseases, where sEng levels are increased.
2020-04-23 | PXD016228 | Pride
Project description:Preeclampsia (PE), which affects 4-8% of human pregnancies, causes significant maternal and neonatal morbidity and mortality. Within the basal plate, placental cytotrophoblasts (CTBs) of fetal origin invade the uterus and extensively remodel the maternal vasculature. In PE, CTB invasion is often shallow, and vascular remodeling is rudimentary. To better understand possible causes, we conducted a global analysis of gene expression at the maternal-fetal interface in placental samples from women with PE (n = 12; 24-36 wk) vs. samples from women who delivered due to preterm labor with no evidence of infection (n = 11; 24-36 wk), a condition that our previous work showed is associated with normal CTB invasion. Using the HG-U133A&B Affymetrix GeneChip platform, and statistical significance set at log odds-ratio of B >0, 55 genes were differentially expressed in PE. They encoded proteins previously associated with PE [e.g. Flt-1 (vascular endothelial growth factor receptor-1), leptin, CRH, and inhibin] and novel molecules [e.g. sialic acid binding Ig-like lectin 6 (Siglec-6), a potential leptin receptor, and pappalysin-2 (PAPP-A2), a protease that cleaves IGF-binding proteins]. We used quantitative PCR to validate the expression patterns of a subset of the genes. At the protein level, we confirmed PE-related changes in the expression of Siglec-6 and PAPP-A2, which localized to invasive CTBs and syncytiotrophoblasts. Notably, Siglec-6 placental expression is uniquely human, as is spontaneous PE. The functional significance of these novel observations may provide new insights into the pathogenesis of PE, and assaying the circulating levels of these proteins could have clinical utility for predicting and/or diagnosing PE. Keywords: disease state analysis Basal plate biopsies of preterm labor (24-36 weeks; n=11) and preterm severe preeclampsia (24-36 weeeks; n=12) were isolated and the global gene expression profiles determined using Affymetrix Human GeneChips. Comparisons between the preeclampsia samples and the preterm labor controls revealed genes differentially expressed in preeclampsia.
2009-02-06 | E-GEOD-14722 | biostudies-arrayexpress
Project description:Background: Preeclampsia (PE) is a placental disease characterized by hypertension and proteinuria in pregnant women, which is associated with a high maternal and infantile morbidity. However, circulating biomarkers able to predict the prognosis of PE are lacking. Methods: Thirty-eight women were included in the study. They consisted of 19 patients with PE (13 with severe PE and 6 women with non-severe PE) and 19 gestational age-matched normal pregnancy controls. We measured coagulation pathway, endothelial responses and microparticle release and circulating gene expression in PE patient groups and normotensive controls. Results: The measurement of markers associated with coagulation pathway, endothelial activation and circulating microparticles enabled to discriminate PE from normal pregnancy but were not sufficient to distinguish severe from non-severe PE. PE patients also exhibited a specific transcriptional program distinct from that of control women and subtle differences were observed between severe and non-severe PE. Functional annotation of the up-modulated signature in PE highlighted two main functions related to ribosome and complement. Importantly, we found that 8 genes were specifically up-modulated in severe preeclampsia. Among these genes, the expression of VSIG4 was significantly increased in patients with severe preeclampsia in comparison with controls and patients with non-severe preeclampsia. Conclusion: Using transcriptional signatures of blood samples, we identified the gene encoding the estrogen receptor as a potential diagnostic marker of severe preeclampsia. In addition, the determination of this gene may improve the prognostic assessment of severe preeclampsia. Thirty-eight women were included in the study: 19 patients with PE, including 6 women with non-severe PE and 13 with severe PE, and 19 women with normal pregnancy (NP) selected according to age, weight, smoking status, race, gestational age at the inclusion, and blood pH (Table 1 of manuscript). Women with NP had no history of medical illness or medication, and received routing prenatal care. The diagnostic of PE was based on a blood pressure of M-bM-^IM-% 140/90 mmHg taken twice, uricemia above normal laboratory range (120-420 M-BM-5mol/L), and proteinuria higher than 300 mg in a 24 hour-collection, occurring after 20 gestational weeks in previously normotensive women (Table 2). The criteria used to define severe PE included one of the following conditions: a blood pressure higher than 160/110 mmHg, a proteinuria higher than 1500 mg/24h), a multisystem disorder, maternal cerebral symptoms (seizures, stroke) or intrauterine growth restriction below the 3M-BM-0 percentile. Women with multiple gestations, fetal congenital malformations/chromosomal abnormalities, recent infection, antiphospholipid antibodies, trauma, drug or alcohol abuse during pregnancy, preexisting hypertension, thrombophilia with PE history, or women receiving anticoagulant or antiaggregation therapy were excluded from the study. Two microarrays (one non-severe PE and one normal) were discarded from the analysis for technical reasons. Thus, only 36 microarrays are included here.
2014-05-14 | E-GEOD-48424 | biostudies-arrayexpress
Project description:Background: Preeclampsia (PE) is a placental disease characterized by hypertension and proteinuria in pregnant women, which is associated with a high maternal and infantile morbidity. However, circulating biomarkers able to predict the prognosis of PE are lacking. Methods: Thirty-eight women were included in the study. They consisted of 19 patients with PE (13 with severe PE and 6 women with non-severe PE) and 19 gestational age-matched normal pregnancy controls. We measured coagulation pathway, endothelial responses and microparticle release and circulating gene expression in PE patient groups and normotensive controls. Results: The measurement of markers associated with coagulation pathway, endothelial activation and circulating microparticles enabled to discriminate PE from normal pregnancy but were not sufficient to distinguish severe from non-severe PE. PE patients also exhibited a specific transcriptional program distinct from that of control women and subtle differences were observed between severe and non-severe PE. Functional annotation of the up-modulated signature in PE highlighted two main functions related to ribosome and complement. Importantly, we found that 8 genes were specifically up-modulated in severe preeclampsia. Among these genes, the expression of VSIG4 was significantly increased in patients with severe preeclampsia in comparison with controls and patients with non-severe preeclampsia. Conclusion: Using transcriptional signatures of blood samples, we identified the gene encoding the estrogen receptor as a potential diagnostic marker of severe preeclampsia. In addition, the determination of this gene may improve the prognostic assessment of severe preeclampsia.
2014-05-14 | GSE48424 | GEO
Project description:Background: Platelets may be pivotal mediators of the thrombo-haemorrhagic complications of preeclampsia (PE), linking inflammation and thrombosis with endothelial and vascular dysfunction. While gestational hypertension (GH) falls within the spectrum of hypertensive complications of pregnancy and is a risk factor for preeclampsia, it is unclear what biomarkers distinguish PE from GH. Aim: To identify specific plasma and platelet thrombo-inflammatory biomarkers indicative of preeclampsia and distinguish PE from GH. Methods: We performed multiplex immunoassays, assessed platelet and plasma proteomics and metabolomics data of PE patients, and compared with non-pregnant (NP), healthy pregnant (PC) and GH participants. Results: We report plasma proteins upregulated, enriched plasma metabolites and proteins distinctly overexpressed in platelets of PE and GH compared to NP and PC. Whilst procoagulation in PC may be fibrinogen driven, Inter-Alpha-Trypsin Inhibitors ITIH2 and ITIH3 were enriched in hypertensive complications of pregnancy (PE and GH), and fibronectin and S100A8/9 may be major procoagulant agonists in PE but not GH. In addition, platelet leucine-rich repeat-containing protein 27 and 42 (LRRC27/42) subunits of volume-regulated VRAC anion channels were markedly overexpressed in preeclampsia and may contribute to the heightened glucose sensitivity and the pro-thrombotic tendency of this disorder. Additionally, our multiplex immunoassays confirmed previous reports of increases in preeclampsia plasma cytokines, including SDF-1α, which can directly activate platelets; but also, i-309 and CTACK cytokines, whose effects on platelets we explored using STRING analysis. Conclusion: We identified biomarkers that may be monitored for preeclampsia onset and progression, and distinguish PE from GH. Also, through protein-protein interactions analysis, we generated a new hypothesis for platelets’ contribution to the thrombo-inflammatory states of preeclampsia.
2022-03-16 | PXD031278 | Pride
Project description:Defective deep placentation, an abnormal transformation of the spiral arteries in the junctional zone of the myometrium, is known to cause significant obstetrical complications such as preeclampsia (PE), fetal growth restriction, and placental infarcts with fetal death. Serological biomarkers to predict and diagnose PE would help antenatal care and reduce the obstetrical complications. To discover biomarkers for prediction of PE, we first performed global proteome profiling of three pairs of maternal plasma samples obtained from the early second trimester pregnant women who subsequently developed PE and controls to identify proteins that were abundant in the patients. We further evaluated the expression changes of PE representing proteins in stored plasma samples of a cohort of subsequently developed PE and their matched controls by MRM assay. We identified both Complement C1s subcomponent (p-value = 0.041) and Protein AMBP (p-value = 0.043) were up-regulated in the cohort of PE plasma samples before manifestation of clinical disease. We propose that these proteins may be involved in the remodeling process of the spiral arteries even before the manifestation of PE. These proteins could be served as potential plasma biomarkers to predict pregnant women at increased risk of developing PE.
2018-07-05 | PXD003419 | Pride
Project description:Placental disorders contribute to pregnancy complications including preeclampsia (PE) and fetal growth restriction (FGR), but debate regarding their specific pathobiology persists. Our objective was to apply transcriptomics with weighted gene correlation network analysis (WGCNA) to further clarify the placental dysfunction in these conditions.
2023-08-25 | GSE203507 | GEO
Project description:Preeclampsia (PE), a multifactorial pregnancy-specific syndrome accounting for up to 8% of pregnancy complications, is a leading cause of maternal and fetal morbidity and mortality and PE is also associated with long-term risk of hypertension and stroke for both the mother and fetus. Currently, the only “cure” is delivery of the baby and placenta, largely because the pathogenesis of preeclampsia is not yet fully understood. Preeclampsia is associated with impaired vascular remodeling at the maternal-fetal interface and placental insufficiency; however, the specific factors that contribute to this impairment have not been identified. To identify potential contributing pathways, we examined temporal transcriptomic changes occurring within the uterus, uterine implantation sites, and placentae from the Dahl salt-sensitive (Dahl S) rat model of superimposed preeclampsia compared to Sprague Dawley (SD) rats. We hypothesized that the Dahl S maternal-fetal interface would exhibit a unique temporal transcriptomic profile unveiling novel biomarkers, therapeutic targets, and mechanistic pathways regarding the development of PE. Our initial study focused on evaluation of genes previously linked to the development PE from using real time quantitative PCR (RT qPCR) and total RNA was isolated from uterus (day 0), uterine implantation sites (days 7, 10, 14), and placenta (days 14 and 20). Subsequently, an unbiased transcriptome analysis was performed at each time point using whole genome microarray to identify novel factors involved in PE. 624, 332, 185 , and 366 genes were found to be differentially expressed on days 0, 7, 10 and 14 respectively, with a Reactome Pathway enrichment for “Fatty acid metabolism, Metabolism of water-soluble vitamins and cofactors, Metabolism, Synthesis of substrates in N-glucan biosynthesis on Day 7”; ”Glycerophospholipid biosynthesis, Phospholipid metabolism, and Metabolism of lipids on Day 10”; and “Metabolism of lipids, Phospholipid metabolism, degradation of the extracellular matrix, Fatty acid metabolism, and Collagen degradation on Day 14” in the Dahl S rat vs. SD. Our data revealed numerous pathways that may play a role in the pathophysiology of spontaneous superimposed PE and allow for further investigation of novel therapeutic targets and biomarker development.
2019-09-10 | GSE130102 | GEO