Abstract

ObjectiveThe 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.MethodsThe 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.ResultsA 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.ConclusionMethylation 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.

Highlights

  • The hypertensive pregnancy disorder preeclampsia is one of the most common causes of maternal and fetal morbidity and mortality in the developed world (Roberts, 2000; Wang et al, 2004)

  • We previously found lower numbers and impaired function of fetal endothelial colony forming cells (ECFC), a late outgrowth sub-class of Endothelial progenitor cells (EPC), in pregnancies complicated by preeclampsia

  • We first compared the methylation patterns of cord blood derived ECFC associated with preeclampsia and normal pregnancy controls by means of the Infinium EPIC BeadChip microarray

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Summary

Introduction

The hypertensive pregnancy disorder preeclampsia is one of the most common causes of maternal and fetal morbidity and mortality in the developed world (Roberts, 2000; Wang et al, 2004). Recent studies suggest that preeclampsia represents an independent, cardiovascular risk factor for the mother, but that the cardiovascular system of the offspring is adversely affected. The affected children display on average significantly higher blood pressure, higher body mass index (BMI) and increased vascular stiffness in the pulmonary and peripheral circulation compared to offspring from uncomplicated pregnancies (Jayet et al, 2010; Davis et al, 2012). Epidemiological studies suggest that cardiovascular disease can originate during fetal development (Barker et al, 1989). The exact molecular mechanisms are still unclear, but epigenetic changes may be involved

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