Hypoxia and Aberrant Uterine Vascular Adaptation in Pregnancy

描述(申请人提供)：妊娠期缺氧是一种常见的母体心血管稳态压力，会导致子宫血管血流动力学异常，增加先兆子痫和胎儿发育异常的风险。最近对绵羊的研究表明，妊娠期慢性低氧导致子宫动脉雌激素受体1(ER1)表达显著降低，并抑制妊娠期间子宫动脉类固醇激素介导的肌张力适应。然而，其分子机制仍然知之甚少。我们的初步研究表明，慢性缺氧增加了子宫动脉中ER1基因启动子的甲基化。DNA甲基化是基因表达模式表观遗传修饰的主要机制。虽然ER1启动子的甲基化已被报道为多种组织类型的生理调节的直接功能，并作为多种类型癌症组织的病理进展的一部分，但对ER1基因在血管平滑肌中的表达模式及其功能影响的表观遗传调控知之甚少。这项拟议的研究将解决我们知识中的这些主要差距，并检验这一假说，即妊娠期慢性缺氧会导致异常的启动子甲基化和ER1基因抑制，从而导致妊娠期间子宫动脉肌源性张力增加。本研究的目的有三个：1)妊娠期长期高原低氧是否增加了导致ER1基因抑制的启动子甲基化；2)长期低氧直接导致了高启动子甲基化和ER1基因抑制；3)低氧介导的启动子甲基化和ER1基因抑制抑制了激素介导的妊娠子宫动脉压力依赖性肌原张力的激素调节。这些结果不仅将显著提高我们对子宫胎盘循环异常的分子机制的认识，从而提高我们对与缺氧相关的妊娠并发症的理解，而且还将为调控ER1基因在血管平滑肌中表达模式的表观遗传学机制提供令人兴奋的新见解，从而全面理解ER1在雌激素介导的血管功能保护作用中的作用。

DESCRIPTION (provided by applicant): Hypoxia during gestation is a common stress to maternal cardiovascular homeostasis and causes aberrant uterine vascular hemodynamics and an increased risk of preeclampsia and abnormal fetal development. Recent studies in sheep have demonstrated that chronic hypoxia during gestation causes a significant decrease in estrogen receptor 1 (ER1) expression in uterine arteries, and inhibits the steroid hormone-mediated adaptation of myogenic tone in uterine arteries in pregnancy. However, the molecular mechanisms remain poorly understood. Our preliminary studies suggest that chronic hypoxia increases promoter methylation of the ER1 gene in the uterine artery. DNA methylation is a chief mechanism in epigenetic modification of gene expression patterns. Although methylation of the ER1 promoter has been reported to occur as a direct function of physiological regulation in several tissue types and as part of a pathological progression of numerous types of cancerous tissues, little is known about the epigenetic regulation of ER1 gene expression pattern in vascular smooth muscle and its functional consequences. The proposed studies will address these major gaps in our knowledge and test the hypothesis that chronic hypoxia during gestation causes aberrant promoter methylation and ER1 gene repression resulting in heightened myogenic tone of the uterine artery in pregnancy. Three specific aims are proposed to determine whether: 1) long-term high altitude hypoxia during gestation increases the promoter methylation resulting in ER1 gene repression, 2) prolonged hypoxia has direct causal effects on the heightened promoter methylation and ER1 gene repression, and 3) hypoxia- mediated promoter methylation and ER1 gene repression inhibit the steroid hormone-mediated adaptation of pressure-dependent myogenic tone in the uterine arteries in pregnancy. The results will not only significantly advance our knowledge of the molecular mechanisms underlying aberrant uteroplacental circulation and hence improve our understanding of the pregnancy complications associated with hypoxia, but also provide exciting novel insights into the epigenetic mechanisms regulating ER1 gene expression patterns in vascular smooth muscle and hence a comprehensive understanding of the role of ER1 in the estrogen-mediated protective effect of vascular function in general.