Mechanisms of uterine artery hemodynamics adaptation to pregnancy and gestational hypoxia

项目摘要 怀孕与子宫血流量的显著增加有关，而子宫血流量是正常胎儿所必需的。 对于母亲的发展和心血管健康也是如此。怀孕期间的缺氧有很深的影响 子宫动脉血流动力学适应不良反应，增加妊娠并发症发生率 包括先兆子痫和胎儿宫内发育受限。早先对妊娠动物模型的研究 适应高原低氧的绵羊表明，怀孕的母羊与怀孕的母羊相似 因为它们都表现出子宫血管阻力的增加和母体血液的升高 应对妊娠低氧的压力。然而，其背后的机制仍有许多未知之处。 妊娠期母体心血管对慢性低氧的适应不良。我们在绵羊身上的初步研究 提示了单体G蛋白Rad抑制L型钙通道的一种新机制 子宫动脉中的电流。L钙通道作为钙离子内流的主要途径，是钙离子内流的重要途径 用于血管平滑肌收缩，并在调节器官血流和动脉方面发挥中心作用 压力。我们发现绵羊和人类的Rad基因启动子都有多种雌激素反应元件 (Eres)，提示性类固醇激素在调节Rad基因表达中具有很强的机制。 子宫动脉。此外，rna-seq分析显示rad基因下调。 高原低氧习服妊娠绵羊子宫动脉的表达。重要的是，我们 妊娠期慢性低氧抑制妊娠诱导的Rad蛋白上调 绵羊子宫动脉CaV1.2通道电流的表达和增加。这些令人兴奋的发现和许多 高度新颖的线索为我们提供了强有力的科学前提，通过推出 旨在了解Rad调控的分子和表观遗传机制的新的研究热点 CaV1.2通道电流和子宫血管对妊娠的适应性和表型编程 妊娠期缺氧。这项拟议的研究将在一种独特的怀孕绵羊动物模型中进行 妊娠期高海拔(3801米/12,470英尺)低氧。拟议研究的总体假设是 RAD是一种新的调节机制，在L CaV1.2钙离子的调节中起着至关重要的作用 通道电流与子宫血管对妊娠和妊娠低氧的适应。建议进行的研究 具有较强的科学性前提，具有新颖的概念框架和机械论方法。它将提供 对子宫血管适应妊娠的基本机制的新见解，将具有重大意义 影响我们对妊娠并发症的病理生理机制的理解，包括 由妊娠低氧引起的先兆子痫。重要的是，子宫动脉血流动力学和 母羊和母羊对妊娠低氧的血压反应 以及性类固醇激素可能调节RAD基因的常见机制，将提供急需的 拟议的研究在了解产妇心血管并发症方面的翻译相关性 对妊娠期缺氧的反应。

Project Summary Pregnancy is associated with a striking increase of uterine blood flow that is essential for normal fetal development as well as for cardiovascular well-being of the mother. Hypoxia during pregnancy has profound adverse effects on uterine artery hemodynamics adaptation, increasing incidence of pregnancy complications including preeclampsia and fetal intrauterine growth restriction. Previous studies in an animal model of pregnant sheep acclimatized to high altitude hypoxia demonstrated that pregnant ewes were similar to pregnant women in that they both showed an increase in uterine vascular resistance and elevation in maternal systemic blood pressure in response to gestational hypoxia. Yet, much remains unknown of the mechanisms underlying maternal cardiovascular maladaptation to chronic hypoxia during pregnancy. Our preliminary study in sheep suggests a highly novel mechanism of a monomeric G protein, Rad in inhibition of L-type CaV1.2 calcium channel currents in the uterine artery. The L-type CaV1.2 calcium channel, as the major pathway of Ca2+ influx, is essential for vascular smooth muscle contractions and plays a central role in regulating organ blood flow and arterial pressure. We identify that both ovine and human Rad gene promoters have multiple estrogen response elements (EREs), suggesting a robust mechanism of sex steroid hormones in the regulation of Rad gene expression in the uterine artery. In addition, the approach of RNA-seq analysis revealed a downregulation of Rad gene expression in uterine arteries of pregnant ewes acclimatized to high altitude hypoxia. Of importance, we demonstrated that chronic hypoxia during gestation abrogated pregnancy-induced upregulation of Rad protein expression and increased CaV1.2 channel currents in ovine uterine arteries. These exciting findings and many highly novel leads provide a strong scientific premise for us to move the field forward significantly by launching a new focus of research aimed at understanding the molecular and epigenetic mechanisms of Rad in regulating CaV1.2 channel currents and phenotypic programming of uterine vascular adaptation to pregnancy and gestational hypoxia. The proposed study will be conducted in a unique animal model of pregnant sheep exposed to high altitude (3801 m/12,470 ft) hypoxia during gestation. The overall hypothesis of the proposed study is that Rad is a novel regulatory mechanism and plays an essential role in the regulation of L-type CaV1.2 calcium channel currents and uterine vascular adaptation to pregnancy and gestational hypoxia. The proposed study has the strong scientific premise with a novel conceptual framework and mechanistic approach. It will provide new insights into fundamental mechanisms in uterine vascular adaptation to pregnancy, and will have a major impact on our understanding of pathophysiologic mechanisms underlying pregnancy complications including preeclampsia caused by gestational hypoxia. Of importance, the similarity in uterine artery hemodynamics and maternal blood pressure responses to gestational hypoxia between pregnant ewes and pregnant women, as well as likely common mechanisms of Rad gene regulation by sex steroid hormones, will provide much needed translational relevance of the proposed study in the understanding of maternal cardiovascular complications in response to hypoxia during pregnancy.