Hypoxia and Aberrant Uterine Vascular Adaptation in Pregnancy

描述（由申请方提供）：妊娠期间缺氧是母体心血管稳态的常见应激，可导致子宫血管血流动力学异常，并增加先兆子痫和胎儿发育异常的风险。近年来对绵羊的研究表明，妊娠期慢性缺氧可导致子宫动脉中雌激素受体1（ER 1）表达显著降低，并抑制类固醇激素介导的妊娠期子宫动脉肌源性张力的适应。然而，分子机制仍然知之甚少。我们的初步研究表明，慢性缺氧增加子宫动脉ER1基因启动子甲基化。DNA甲基化是基因表达模式表观遗传修饰的主要机制。虽然已经报道了ER 1启动子的甲基化作为生理调节的直接功能在几种组织类型中发生，并且作为许多类型的癌组织的病理进展的一部分，但是关于血管平滑肌中ER 1基因表达模式的表观遗传调节及其功能后果知之甚少。拟议的研究将解决我们知识中的这些主要空白，并检验妊娠期间慢性缺氧导致异常启动子甲基化和ER 1基因抑制导致妊娠期子宫动脉肌源性张力升高的假设。提出了三个具体目标，以确定：1）妊娠期长期高原低氧可增加ER 1基因启动子甲基化，导致ER 1基因抑制，2）长期低氧对ER 1基因启动子甲基化和ER 1基因抑制的增加有直接因果关系，低氧介导的启动子甲基化和ER 1基因抑制抑制类固醇激素介导的压力适应。妊娠期子宫动脉的肌张力依赖性。这些结果不仅将显著提高我们对异常子宫胎盘循环的分子机制的认识，从而提高我们对缺氧相关妊娠并发症的理解，而且还为调节血管平滑肌中ER 1基因表达模式的表观遗传机制提供了令人兴奋的新见解，从而全面了解了ER 1在雌激素调节中的作用。介导的血管功能保护作用。

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.