Preeclampsia-Associated Alteration of DNA Methylation in Fetal Endothelial Progenitor Cells

Abstract

Objective The pregnancy complication preeclampsia represents an independent risk factor for cardiovascular disease. Our previous research shows a diminished function of fetal endothelial colony-forming cells (ECFC), a proliferative subgroup of endothelial progenitor cells (EPC) in preeclampsia. The aim of this study was to further investigate whether DNA methylation of fetal EPC is affected in preeclampsia. Methods The genomic methylation pattern of fetal ECFC from uncomplicated and preeclamptic pregnancies was compared for 865918 CpG sites, and genes were classified into gene networks. Low and advanced cell culture passages were compared to explore whether expansion of fetal ECFC in cell culture leads to changes in global methylation status and if methylation characteristics in preeclampsia are maintained with increasing passage. Results A differential methylation pattern of fetal ECFC from preeclampsia compared to uncomplicated pregnancy was detected for a total of 1266 CpG sites in passage 3, and for 2362 sites in passage 5. Key features of primary networks implicated by methylation differences included cell metabolism, cell cycle and transcription and, more specifically, genes involved in cell-cell interaction and Wnt signaling. We identified an overlap between differentially regulated pathways in preeclampsia and cardiovascular system development and function. Cell culture passages 3 and 5 showed similar gene network profiles, and 1260 out of 1266 preeclampsia-associated methylation changes detected in passage 3 were confirmed in passage 5. Conclusion Methylation modification caused by preeclampsia is stable and detectable even in higher cell culture passages. An epigenetically modified endothelial precursor may influence both normal morphogenesis and postnatal vascular repair capacity. Further studies on epigenetic modifications in complicated pregnancies are needed to facilitate development of EPC based therapies for cardiovascular alterations.

Novel insights for the role of nitric oxide in placental vascular function during and beyond pregnancy

“…In contrast, differential DNA methylation in HUVEC has been described between twin pairs (Ollikainen et al, 2010), suggesting that even subtle environmental variations impact the endothelial epigenome. In this regard, progenitor ECs isolated from cord blood show that PE impinges an epigenetic signature in cardiovascular development pathways preserved under culture conditions (Brodowski et al, 2019). A similar effect has been reported in progenitor ECs from preterm neonates at a single-gene level in which angiogenic mediators are negatively programmed (Vinci et al, 2017).…”

The Role of Epigenetics in Placental Development and the Etiology of Preeclampsia

“…Hypomethylation in the D-loop may lead to increased mitochondrial replication explaining the pathological increase of mitochondrial DNA. Methylation assay in endothelial colony-forming cells present in cord blood from PE presents differential methylation level in genes related to RNA metabolic processes, cellular protein modification processes and in positive regulation transcription, as assessed with the EPIC Illumina array, interrogating over 850,000 CpG [222]. However, at later passages, an increased number of genes are abnormally methylated.…”

MicroRNA Profiles of Maternal and Neonatal Endothelial Progenitor Cells in Preeclampsia

“…Our own research shows that endothelial colony-forming cells (ECFC), a proliferative EPC subtype, are reduced in cord blood of infants born to women with preeclampsia [12]. Further, we described key functional differences and differential DNA methylation profiles between ECFC obtained from cord blood of preeclamptic compared to healthy pregnancies [12,13].…”