An epigenetic basis for maternal vascular adaptation to pregnancy

 说明(申请人提供)：心血管疾病是女性死亡的头号原因，孕产史是未来心血管健康的主要预测因素：无并发症妊娠与心血管疾病风险降低相关，而低血压妊娠与显著风险增加相关。目前，尚不清楚怀孕是否只是将女性确定为未来心血管疾病的高危人群，或者怀孕是否实际上改变了未来的风险。我们小组的初步工作表明，大导管动脉(特别是主动脉)的广泛重塑发生在妊娠期间，这种重塑涉及到主动脉血管平滑肌的表观遗传学变化。基于这些发现，我们假设表观遗传改变对于血管适应是必要的，并且妊娠对主动脉的任何持续影响都伴随着表观遗传变化。我们建议通过以下具体目标来检验这一假说：1)确定主动脉中DNA甲基化和羟甲基化的整体水平是否反映了怀孕期间发生的生理和形态变化，并评估这些表观遗传变化在产后的持久性。通过系统地评估实验小鼠主动脉的表观遗传学、生理学、形态学和基因表达参数，我们将测试与怀孕相关的表观遗传学DNA修改是否真的反映了其他适应性变化。2)检测Tet基因下调和伴随的表观遗传学改变是否在妊娠期VSM表型转换和主动脉适应中是必要的。我们将利用慢病毒迫使Tet基因在小鼠的VSM中表达，以直接验证主动脉重塑依赖于Tet基因下调的假说。相关性：拟议的研究与女性的健康高度相关，因为它们承诺揭示一种新的分子机制，通过这种机制，怀孕可以对母亲的血管产生持续影响，从而影响她患心血管疾病的长期风险。

 DESCRIPTION (provided by applicant): Cardiovascular disease is the number one cause of death in women, and pregnancy history is a major predictor of future cardiovascular health: Uncomplicated pregnancy is associated with diminshed risk of cardiovascular disease, and hyptertensive pregnancy is associated with a marked increased risk. At present, it is unknown whether pregnancy meerly identifies women with a high risk of future cardiovascular disese or whether pregancy actually alters future risk. Preliminary work by our group indicates that extensive remodeling of large conduit arteries (specifically the aorta) occurs during pregnancy and that this remodeling involves epigenetic changes in the vascular smooth muscle of the aorta. Based on these findings, we hypothesize that epigenetic modification is necessary for vascular adaptation and that any persistent effects of pregnancy on the aorta are accompanied by epigenetic changes. We propose to test this hypothesis through the following specific aims: 1) To determine whether global levels of DNA methylation and hydroxymethylation in the aorta reflect physiologic and morphologic changes that occur in pregnancy, and to assess the persistence of these epigenetic changes post partum. By systematically assessing epigenetic, physiologic, morphologic and gene expression parameters of the aorta of the laboratory mouse, we will test whether pregnancy related epigenetic DNA modifications indeed mirror other adaptive changes. 2) To test whether Tet gene down-regulation and concomitant epigenetic change is necessary for VSM phenotype switching and aortic adaptation during pregnancy. We will use lentivirus in order to force expression of Tet genes in VSM in the mouse, in order to directly test the hypothesis that aortic remodeling depends on Tet gene down-regulation. Relevance: The proposed studies are highly relevant to women's health, because they promise to shed light on a novel molecular mechanism through which pregnancy can have persistent effects on the mother's blood vessels and thereby impact her long-term risk of developing cardiovascular disease.