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

有先兆子痫（PE）病史的女性在以后的生活中患高血压和心血管疾病的风险增加。最近的研究结果表明，后代的心血管系统也会受到不利影响。流行病学研究表明，心血管疾病可起源于胎儿发育期间。确切的分子机制尚不清楚，但可能涉及表观遗传和遗传变化。我们之前的研究表明，妊娠合并PE时，胎儿内皮集落形成细胞（ECFC）的集落数量减少，功能受损，ECFC是内皮祖细胞（EPC）的一个晚期分支亚类。此外，我们检测到与未并发症妊娠相比，PE胎儿ECFC的甲基化模式存在差异。EPC在血管稳态和发育中起着重要的作用。在非怀孕人群中，循环EPC的减少与心血管风险的增加有关，这突出了EPC在维持内皮功能中的重要性。它们的损伤也可能反映了PE后后代的血管健康状况。考虑到基于EPC的细胞治疗的潜力，本研究的目的是通过研究影响与心血管损伤相关的特定基因表达变化的因素以及如何挽救表观遗传和遗传改变来探索PE中胎儿EPCs是如何受损的。在不同的工作包中，我们将。比较子痫前期和健康妊娠后代脐带血来源EPC的转录组谱，并将结果与先前关于甲基化差异的结果以及内皮功能障碍/心血管疾病受试者已知的转录组异常联系起来。确定剪接模式，并确定PE和健康妊娠的脐带血来源EPC的特定替代剪接变体。3 .确定长链非编码（lnc） RNA，并鉴定PE和健康妊娠脐带血来源EPC的特异性lnc RNA谱。总结体外基因表达变化，研究其在内皮细胞模型系统中的功能影响，探索非编码rna基因失调对EPC功能的影响，并开发序列特异性干扰方法以恢复功能。他汀类药物对这些终点的影响将以普伐他汀为参比化合物进行研究。

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.