Distinct placental molecular processes associated with early-onset and late-onset preeclampsia

Ren, Zhonglu; Gao, Yunfei; Gao, Yue; Liang, Guanmei; Chen, Qian; Jiang, Sijia; Yang, Xiaoxue; Fan, Cui-Xia; Wang, Haizhen; Wang, Jing; Shi, Yi‐Wu; Xiao, Chaoqun; Zhong, Ming; Yang, Xinping

doi:10.7150/thno.56141

Cited by 41 publications

(19 citation statements)

References 98 publications

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“…EOPE is often associated with impaired placentation as early as the first trimester, while abnormalities in the maternal vasculature are associated with LOPE. Previous studies have shown that EOPE and LOPE have different gene expression profiles underlying the differential pathogenesis of the two PE subtypes [ 26 , 27 ]. In this study, we observed similar results.…”

Section: Discussionmentioning

confidence: 99%

Expression profiles and functions of ferroptosis-related genes in the placental tissue samples of early- and late-onset preeclampsia patients

Yang

Wang

Ding

et al. 2022

BMC Pregnancy Childbirth

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Background The accumulation of reactive oxygen species (ROS) resulting from upregulated levels of oxidative stress is commonly implicated in preeclampsia (PE). Ferroptosis is a novel form of iron-dependent cell death instigated by lipid peroxidation that likely plays an important role in PE pathogenesis. This study aimed to investigate the expression profiles and functions of ferroptosis-related genes (FRGs) in early-onset preeclampsia (EOPE) and late-onset preeclampsia (LOPE). Methods Gene expression data and clinical information were downloaded from the Gene Expression Omnibus (GEO) database. The “limma” R package was used to screen differentially expressed genes. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) and protein–protein interaction (PPI) network analyses were conducted to investigate the bioinformatics functions and molecular interactions of significantly different FRGs. Quantitative reverse transcription polymerase chain reaction (RT-qPCR) was used to verify the expression of hub FRGs in PE. Results A total of 4215 differentially expressed genes (DEGs) were identified between EOPE and preterm cases while 556 DEGs were found between LOPE and term controls. Twenty significantly different FRGs were identified in EOPE subtypes, while only 3 FRGs were identified in LOPE subtypes. Functional enrichment analysis revealed that the differentially expressed FRGs were mainly involved in EOPE and enriched in hypoxia- and iron-related pathways, such as the response to hypoxia, iron homeostasis and iron ion binding process. PPI network analysis and verification by RT-qPCR resulted in the identification of the following five FRGs of interest: FTH1, HIF1A, FTL, MAPK8 and PLIN2. Conclusions EOPE and LOPE have distinct underlying molecular mechanisms, and ferroptosis may be mainly implicated in the pathogenesis of EOPE. Further studies are necessary for deeper inquiry into placental ferroptosis and its role in the pathogenesis of EOPE.

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Section: Discussionmentioning

confidence: 99%

Expression profiles and functions of ferroptosis-related genes in the placental tissue samples of early- and late-onset preeclampsia patients

Yang

Wang

Ding

et al. 2022

BMC Pregnancy Childbirth

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“…As we’ve shown that NR4A2 expression is altered between preterm and term gestations, we suggest that this disparity is likely due to gestational differences. Further, early- and late-onset preeclampsia have distinct molecular processes, with the early-onset cases associated with increased severity 42 , 43 . Our study overcomes this potential confounder by assessing the harder to source clinical samples exclusively from cases of preterm preeclampsia delivering ≤ 34 weeks.…”

Section: Discussionmentioning

confidence: 99%

NR4A2 expression is not altered in placentas from cases of growth restriction or preeclampsia, but is reduced in hypoxic cytotrophoblast

Alwis

Beard

Binder

et al. 2021

Sci Rep

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Nuclear Receptor Subfamily 4 Group A Member 2 (NR4A2) transcripts are elevated in the circulation of individuals whose pregnancies are complicated by preterm fetal growth restriction (FGR). In this paper, we show that the cases with preeclampsia (PE) have increased circulating NR4A2 transcripts compared to those with normotensive FGR. We aimed to establish whether the dysfunctional placenta mirrors the increase in NR4A2 transcripts and further, to uncover the function of placental NR4A2. NR4A2 expression was detected in preterm and term placental tissue; expressed higher at term. NR4A2 mRNA expression and protein were not altered in placentas from preterm FGR or PE pregnancies. Hypoxia (1% O2 compared to 8% O2) significantly reduced cytotrophoblast NR4A2 mRNA expression, but not placental explant NR4A2 expression. Silencing cytotrophoblast NR4A2 expression under hypoxia (via short interfering (si)RNAs) did not alter angiogenic Placental Growth Factor, nor anti-angiogenic sFlt-1 mRNA expression or protein secretion, but increased expression of cellular antioxidant, oxidative stress, inflammatory, and growth genes. NR4A2 expression was also not altered in a model of tumour necrosis factor-α-induced endothelial dysfunction, or with pravastatin treatment. Further studies are required to identify the origin of the circulating transcripts in pathological pregnancies, and investigate the function of placental NR4A2.

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“…Some studies are sorting out the relationship between PE subtypes and specific genes. 10 , 11 By analyzing the RNA profiles of 302 human placenta samples, Gong et al 12 demonstrated that elevated serum levels of follistatin-like 3 (FSTL3) in pregnant women were predictive of subsequent PE and fetal growth restriction (FGR). Moreover, reported by recent studies, plasma cell-free RNA (cfRNA) could exhibit specific patterns to indicate normal pregnancy progression and serve as the biomarker to detect the risk of PE months before clinical manifestations.…”

Section: Introductionmentioning

confidence: 99%

Gene Expression Network Analysis Identifies Potential Targets for Prevention of Preeclampsia

Yu¹,

Zhao²,

Sun³

et al. 2022

IJGM

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Objective Preeclampsia (PE) is a pregnancy-specific multisystem disease as well as an important cause of maternal and perinatal death. This study aimed to analyze the placental transcriptional data and clinical information of PE patients available in the published database and predict the target genes for prevention of PE. Methods The clinical information and corresponding RNA data of PE patients were downloaded from the GEO database. Cluster analysis was performed to examine the correlation between different genotyping genes and clinical manifestations. Then, bioinformatic approaches including GO, KEGG, WGCNA, and GSEA were employed to functionally characterize candidate target genes involved in pathogenesis of PE. Results Two PE datasets GSE60438 and GSE75010 were obtained and combined, thereby providing the data of 205 samples in total (100 non-PE and 105 PE samples). After eliminating the batch effect, we grouped and analyzed the integrated data, and further performed GSEA analysis. It was found that the genes in group 1 and group 2 were different from those in normal samples. Moreover, WGCNA analysis revealed that genes in group 1 were up-regulated in turquoise module, including SASH1 , PIK3CB and FLT-1 , while genes in group 2 were up-regulated in the blue and brown modules. We further conducted GO and KEGG pathway enrichment analyses and found that the differential genes in turquoise module were mainly involved in biological processes such as small molecular catabolic process, while being highly enriched in pathways, including MAPK signaling pathway and Rap1 signaling pathway. Conclusion FLT-1 was conventionally used to predict PE risk, and sFLT-1 could also be used as an indicator to evaluate PE treatment effect. As a candidate biomarker for predicting PE, SASH1 may participate in proliferation, migration, invasion and epithelial mesenchymal transformation of human trophoblast cells by regulating MAPK pathway and Rap1 signaling pathway, thus affecting the progression of PE. The mechanism allowing PIK3CB to regulate PE development was not clear, while the gene could be another candidate biomarker for PE risk prediction. This is an exploratory study and our findings were still required verification in further studies.

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Distinct placental molecular processes associated with early-onset and late-onset preeclampsia

Cited by 41 publications

References 98 publications

Expression profiles and functions of ferroptosis-related genes in the placental tissue samples of early- and late-onset preeclampsia patients

Expression profiles and functions of ferroptosis-related genes in the placental tissue samples of early- and late-onset preeclampsia patients

NR4A2 expression is not altered in placentas from cases of growth restriction or preeclampsia, but is reduced in hypoxic cytotrophoblast

Gene Expression Network Analysis Identifies Potential Targets for Prevention of Preeclampsia

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