Regulatory mechanisms of gene expression linking impaired vascular health with preeclamptic pregnancies

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Women with a history of preeclampsia (PE) have an increased risk of hypertension and cardiovascular disease later in life. Recent findings imply that the cardiovascular system of the offspring is also adversely affected. Epidemiological studies suggest that cardiovascular disease can originate during fetal development. The exact molecular mechanisms are still unclear, but epigenetic and genetic changes may be involved. Our previous research shows lower colony 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 PE. Additionally, we detected a differential methylation pattern of fetal ECFC from PE compared to uncomplicated pregnancy. EPC play an important role in vascular homeostasis and development. In the non-pregnant population, reduction in circulating EPC is associated with increased cardiovascular risks, highlighting the importance of EPC in the maintenance of endothelial function. Their impairment might also reflect the vascular health of the offspring after PE. Considering the potential of cell therapies based on EPC, the objectives of this study are to explore how fetal EPCs are compromised in PE by investigating which factors impact specific gene expression changes associated with cardiovascular impairment and how epigenetic and genetic alterations can be rescued. In different work packages, we will1. Compare transcriptomic profiles of cord-blood derived EPC from offspring of preeclamptic and healthy pregnancies and correlate the results with previous results on differential methylation and with transcriptomic abnormalities to be known of subjects with endothelial dysfunction/cardiovascular disease.2. Determine splicing patterns and identify specific alternative splice-variants of cord blood derived EPC of PE and healthy pregnancies.3. Determine long-non-coding (lnc) RNAs and identify specific lnc RNA profiles of cord blood derived EPC of PE and healthy pregnancies.4. Recapitulate gene expression changes in vitro, investigate their functional consequences in endothelial cellular model systems and explore the impact of dysregulated non-coding RNAs genes on EPC function and develop methods of sequence-specific interference to restore functionality. The effect of statins on these endpoints will be investigated using pravastatin as the reference compound.