Analysis of the Placental Tissue Transcriptome of Normal and Preeclampsia Complicated Pregnancies (original) (raw)
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Placenta, 2009
Background: Preeclampsia is a pregnancy-specific disorder that remains a leading cause of maternal, fetal and neonatal morbidity and mortality, and is associated with risk for future cardiovascular disease. There are no reliable predictors, specific preventative measures or treatments other than delivery. A widely held view is that the antecedents of preeclampsia lie with impaired placentation in early pregnancy. Accordingly, we hypothesized dysregulation of global gene expression in first trimester placentas of women who later manifested preeclampsia.
Differential Placental Gene Expression in Severe Preeclampsia
Placenta, 2009
We investigated the global placental gene expression profile in severe preeclampsia. Twenty-one women were randomly selected from 50 participants with uncomplicated pregnancies to match 21 patients with severe preeclampsia. A 30 K Human Genome Survey Microarray v.2.0 (Applied Biosystems) was used to evaluate the gene expression profile. After RNA isolation, five preeclamptic placentas were excluded due to poor RNA quality. The series composed of 37 hybridizations in a one-channel detection system of chemiluminescence emitted by the microarrays. An empirical Bayes analysis was applied to find differentially expressed genes. In preeclamptic placentas 213 genes were significantly (fold-change ! 2 and p 0.01) up-regulated and 82 were down-regulated, compared with normal placentas. Leptin (40 fold), laeverin (10 fold), different isoforms of b-hCG (3-6 fold), endoglin (4 fold), FLT1 (3 fold) and FLT4 (2 fold) were up-regulated. PDGFD was down-regulated (2 fold). Several differentially expressed genes were associated with Alzheimer disease, angiogenesis, Notch-, TGFb-and VEGF-signalling pathways. Sixteen genes best discriminated preeclamptic from normal placentas. Comparison between early-(<34 weeks) and late-onset preeclampsia showed 168 differentially expressed genes with oxidative stress, inflammation, and endothelin signalling pathways mainly involved in early-onset disease. Validation of the microarray results was performed by RT-PCR, quantitative urine hCG measurement and placental histopathologic examination. In summary, placental gene expression is altered in preeclampsia and we provide a comprehensive list of the differentially expressed genes. Placental gene expression is different between early-and late-onset preeclampsia, suggesting differences in pathophysiology.
Differential placental gene expression in preeclampsia
American Journal of Obstetrics and Gynecology, 2008
Objective-Candidate genes associated with preeclampsia have not been fully described. We conducted microarray and confirmatory QRT-PCR studies to investigate global placental gene expression in preeclampsia. Study design-RNA was extracted from placental samples collected from 18 preeclampsia cases and 18 normotensive controls. Oligonucleotide probes representing 22,000 genes were used to measure gene expression in each sample. Differential gene expression was evaluated using Students T-test, fold change assessment and Significance Analysis of Microarrays (SAM). Functions and functional relationships of differentially expressed genes were evaluated. Results-Genes (n=58) participating in immune system, inflammation, oxidative stress, signaling, growth and development pathways were differentially expressed in preeclampsia. These genes include previously described candidate genes (such as LEP), potential candidate genes with related functions (such as CYP11A) and novel genes (such as CDKN1C). Conclusion-Expression of genes (both candidate and novel) with diverse functions is associated with preeclampsia risk, reflecting the complex pathogenesis.
Scientific reports, 2015
One in five pregnant women suffer from gestational complications, prevalently driven by placental malfunction. Using RNASeq, we analyzed differential placental gene expression in cases of normal gestation, late-onset preeclampsia (LO-PE), gestational diabetes (GD) and pregnancies ending with the birth of small-for-gestational-age (SGA) or large-for-gestational-age (LGA) newborns (n = 8/group). In all groups, the highest expression was detected for small noncoding RNAs and genes specifically implicated in placental function and hormonal regulation. The transcriptome of LO-PE placentas was clearly distinct, showing statistically significant (after FDR) expressional disturbances for hundreds of genes. Taqman RT-qPCR validation of 45 genes in an extended sample (n = 24/group) provided concordant results. A limited number of transcription factors including LRF, SP1 and AP2 were identified as possible drivers of these changes. Notable differences were detected in differential expression s...
Gene expression profiling of human placentas from preeclamptic and normotensive pregnancies
Molecular Human Reproduction, 2006
The aim of this study was to investigate patterns of gene expression in placental samples from patients with preeclampsia (PE), persistent bilateral uterine artery notching (without PE), and normal controls. This study included placental tissue from nine women with PE, seven with uncomplicated pregnancies and five with bilateral uterine artery notching in Doppler velocimetry tracings. Human cDNA microarrays with 6500 transcripts/genes were used and the results verified with real-time PCR and in-situ hybridization. Multidimensional scaling method and random permutation technique demonstrated significant differences among the three groups examined. Within the 6.5K arrays, 6198 elements were unique cDNA clones representing 5952 unique UniGenes and 5695 unique LocusLinks. Multidimensional scaling plots showed 5000 genes that met our quality criteria; among these, 366 genes were significantly different in at least one comparison.
Molecular & Cellular Proteomics, 2011
Preeclampsia (PE) adversely impacts ϳ5% of pregnancies. Despite extensive research, no consistent biomarkers or cures have emerged, suggesting that different molecular mechanisms may cause clinically similar disease. To address this, we undertook a proteomics study with three main goals: (1) to identify a panel of cell surface markers that distinguish the trophoblast and endothelial cells of the placenta in the mouse; (2) to translate this marker set to human via the Human Protein Atlas database; and (3) to utilize the validated human trophoblast markers to identify subgroups of human preeclampsia. To achieve these goals, plasma membrane proteins at the blood tissue interfaces were extracted from placentas using intravascular silica-bead perfusion, and then identified using shotgun proteomics. We identified 1181 plasma membrane proteins, of which 171 were enriched at the maternal blood-trophoblast interface and 192 at the fetal endothelial interface with a 70% conservation of expression in humans. Three distinct molecular subgroups of human preeclampsia were identified in existing human microarray data by using expression patterns of trophoblast-enriched proteins. Analysis of all misexpressed genes revealed divergent dysfunctions including angiogenesis (subgroup 1), MAPK signaling (subgroup 2), and hormone biosynthesis and metabolism (subgroup 3). Subgroup 2 lacked expected changes in known preeclampsia markers (sFLT1, sENG) and uniquely overexpressed GNA12. In an independent set of 40 banked placental specimens, GNA12 was overexpressed during preeclampsia when co-incident with chronic hypertension. In the current study we used a novel translational analysis to integrate mouse and human trophoblast protein expression with human microarray data. This strategy identified distinct molecular pathologies in human preeclampsia. We conclude that clinically similar preeclampsia patients exhibit divergent placental gene expression profiles thus implicating divergent molecular mechanisms in the origins of this disease. Molecular & Cellular Pro
Gene expression profiling of pre-eclamptic placentae by RNA sequencing
Scientific Reports, 2015
Pre-eclampsia is a common and complex pregnancy disorder that often involves impaired placental development. In order to identify altered gene expression in pre-eclamptic placenta, we sequenced placental transcriptomes of nine pre-eclamptic and nine healthy pregnant women in pools of three. The differential gene expression was tested both by including all the pools in the analysis and by excluding some of the pools based on phenotypic characteristics. From these analyses, we identified altogether 53 differently expressed genes, a subset of which was validated by qPCR in 20 cases and 19 controls. Furthermore, we conducted pathway and functional analyses which revealed disturbed vascular function and immunological balance in pre-eclamptic placenta. Some of the genes identified in our study have been reported by numerous microarray studies (BHLHE40, FSTL3, HK2, HTRA4, LEP, PVRL4, SASH1, SIGLEC6), but many have been implicated in only few studies or have not previously been linked to pr...
Bjog-an International Journal of Obstetrics and Gynaecology, 2010
Please cite this paper as: Sekizawa A, Purwosunu Y, Farina A, Shimizu H, Nakamura M, Wibowo N, Rizzo N, Okai T. Prediction of pre-eclampsia by an analysis of placenta-derived cellular mRNA in the blood of pregnant women at 15–20 weeks of gestation. BJOG 2010;117:557–564.Objective A panel of cellular mRNA markers was used to predict the occurrence of pre-eclampsia in pregnant women at 15–20 weeks of gestation.Design Prospective cohort study.Setting The Department of Obstetrics and Gynaecology, University of Indonesia, Cipto Mangunkusumo National Hospital, Indonesia.Sample Peripheral blood samples from asymptomatic pregnant women.Methods Among 660 women, 62 developed pre-eclampsia at later gestation (pre-eclampsia group) and each case was matched with five controls. Therefore, the RNA expression levels in the cellular component of maternal blood in 62 women with pre-eclampsia were compared with those in 310 controls.Main outcome measures The cellular RNA expression levels of genes related to angiogenesis and oxidative stress were compared between pre-eclampsia and control groups. A receiver operating characteristic (ROC) curve was used to analyse the sensitivity of each available marker. A logistic regression analysis was performed to calculate the odds for each woman to be classified as a case.Results The univariate ROC analysis identified soluble vascular endothelial growth factor receptor-1 (Flt-1) and endoglin (ENG) as the markers with the highest sensitivity. The best multivariate model was obtained by combining Flt-1, ENG, placental growth factor (PlGF) and parity. The relative ROC curve yielded a sensitivity of 66% at a 10% 1 − specificity rate with an area under the curve of 0.884 (P < 0.001).Conclusion A panel of cellular mRNA markers in maternal blood can predict the development of pre-eclampsia long before clinical onset.
Preeclampsia leads to dysregulation of various signaling pathways in placenta
Journal of Hypertension, 2011
Objectives To compare gene expression profiles of placentas from preeclamptic and normal pregnancies. Study design We performed microarray experiments to analyze genome-wide expression profiling for 10 placentas from pregnant women with preeclampsia and 10 placentas from women who experienced noncomplicated pregnancies (CON), and to identify dysregulated signaling pathways as well as genes in preeclampsia. RT-PCR, realtime RT-PCR and/or immunofluorescence analyses were performed to validate the data obtained from microarray experiments. Results Unsupervised hierarchical clustering showed heterogeneity of preeclampsia at the molecular levels, whereas expression profiles of preeclampsia are distinctly different from those of CON. A list of genes which are differentially expressed between preeclampsia and CON included well known preeclampsia markers, such as Flt-1, leptin, HTRA1 and SIGLEC6. Gene Set Enrichment Analysis, a pathway-oriented analysis method for expression profiles, provided evidence that a number of biological activities including pathways that regulate actin cytoskeleton, TGFb signaling, oxidative phosphorylation, and proteasome activity were aberrantly either up-regulated or downregulated in preeclampsia. RT-PCR and real-time-RT-PCR for genes contributing these biological pathways (gene sets) enriched in either CON or preeclampsia reinforced that these biological processes were systemically dysregulated in preeclampsia. Conclusions Genome-wide expression profiles of preeclampsia showed heterogeneous characteristics of preeclampsia at the molecular levels. Dysregulation of genes and biological pathways could contribute to abnormal behavior of preeclmapsia. Our results will help further understand underlying mechanisms by which preeclampsia affects placental physiology. J Hypertens