Hypoxia and Aberrant Uterine Vascular Adaptation in Pregnancy

描述（由申请人提供）：妊娠期缺氧是母体心血管稳态的常见压力，导致子宫血管血流动力学异常，增加子痫前期和胎儿发育异常的风险。最近对绵羊的研究表明，妊娠期慢性缺氧导致子宫动脉雌激素受体1 （estrogen receptor 1, ER1）表达显著降低，并抑制妊娠期子宫动脉类固醇激素介导的肌原性张力适应。然而，分子机制仍然知之甚少。我们的初步研究表明，慢性缺氧会增加子宫动脉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。尽管ER1启动子的甲基化已被报道为几种组织类型的生理调节的直接功能，以及许多类型癌组织的病理进展的一部分，但对于血管平滑肌中ER1基因表达模式的表观遗传调控及其功能后果知之甚少。提出的研究将解决这些主要的空白在我们的知识和测试的假设，在妊娠期间慢性缺氧导致异常启动子甲基化和ER1基因抑制，导致子宫动脉在妊娠肌张力升高。我们提出了三个具体的目的来确定：1)妊娠期长期高海拔缺氧是否增加启动子甲基化导致ER1基因抑制，2)长期缺氧是否对启动子甲基化和ER1基因抑制升高有直接的因果影响，3)缺氧介导的启动子甲基化和ER1基因抑制是否抑制妊娠期子宫动脉中类固醇激素介导的压力依赖性肌张力的适应。该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，从而提高我们对与缺氧相关的妊娠并发症的理解，也为血管平滑肌中ER1基因表达模式的调控表观遗传机制提供了令人兴奋的新见解，从而全面了解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. PUBLIC HEALTH RELEVANCE: Hypoxia during gestation is a common stress to maternal cardiovascular homeostasis and increases the risk of preeclampsia and fetal intrauterine growth restriction. The proposed studies will provide new insights into the molecular mechanisms underlying aberrant uteroplacental circulation caused by hypoxia in pregnancy and suggest new direction in the clinical management of the pregnancy complications associated with hypoxia, thereby reducing perinatal morbidity while improving maternal health and neonatal outcome.