Long-Term Hypoxemia and Uterine Vascular Adaptation to Pregnancy

该项目的长期目标是了解慢性疾病不良影响的机制。 妊娠期缺氧对子宫血流影响怀孕期间的慢性缺氧是其中一种 对母体心血管系统和胎儿发育最常见的损害， 先兆子痫和胎儿宫内生长受限的风险增加。先前的研究 表明缺氧对子宫血管反应性有深远的影响，并抑制妊娠诱导 子宫动脉收缩力的适应。虽然分子机制仍然贫乏 最近的研究表明，类固醇激素、雌激素和 孕激素调节子宫动脉压力依赖性肌源性张力， 怀孕压力依赖性肌源性收缩是一种重要的生理机制， 调节基础血管张力，并对器官血流的调节有重要作用。的 初步研究表明，妊娠期长期高原缺氧， 增加了妊娠绵羊子宫动脉的肌源性反应性，消除了 未妊娠和妊娠动物之间子宫动脉中压力诱导的肌源性张力。的 拟议的研究将集中在机制和测试的主要假设，慢性缺氧抑制 类固醇激素（雌激素和孕激素）介导的ERK 1/2和PKC信号转导的适应 通路，导致妊娠期子宫动脉肌源性张力增加。为了验证这个假设， 提出了三个具体目标，以确定是否和在何种程度上长期高原缺氧 1）抑制类固醇介导的ERK 1/2基因表达上调， 子宫动脉中PKC活性的下调，2）抑制类固醇介导的 子宫动脉中的压力依赖性肌源性张力，以及3）慢性缺氧是否有直接影响 子宫动脉中类固醇介导的反应。结果将提供令人兴奋的新颖见解 在生物化学、分子、细胞和病理生理适应机制中， 妊娠期子宫胎盘循环对缺氧的反应，具有明显的临床意义 因为妊娠期慢性缺氧引起的子宫循环适应不良与 胎儿发育异常和母体心血管疾病

The long-term goal of the project is to understand the mechanisms underlying the adverse effect of chronic hypoxia on uterine blood flow in pregnancy. Chronic hypoxia during the course of pregnancy is one of the most common insults to the maternal cardiovascular system and fetal development, and is associated with an increased risk of preeclampsia and fetal intrauterine growth restriction. Previous studies have demonstrated that hypoxia has profound effects on uterine vascular reactivity and inhibits pregnancyinduced adaptation of uterine artery contractility. Although molecular mechanisms remain poorty understood, recent studies have suggested genomic mechanisms of the steroid hormones, estrogen and progesterone in regulating pressure-dependent myogenic tone of the uterine artery in adaptation to pregnancy. Pressure-dependent myogenic contraction is an important physiological mechanism that regulates basal vascular tone and contributes significanfiy to the modulafion of organ blood flow. The preliminary studies demonstrated that long-term high altitude hypoxia during pregnancy significantly increased the myogenic reactivity in the uterine artery of pregnant sheep and eliminated the differences in pressure-induced myogenic tone in uterine arteries between nonpregnant and pregnant animals. The proposed studies will focus on the mechanisms and test the main hypothesis that chronic hypoxia inhibits the steroid hormones (estrogen and progesterone)-mediated adaptation of ERK1/2 and PKC signaling pathways, resulting in increased myogenic tone of the uterine artery in pregnancy. To test this hypothesis, three Specific Aims are proposed to determine whether and to what extent long-term high altitude hypoxia during pregnancy 1) inhibits steroids-mediated upregulation of ERK1/2 gene expression and downregulafion of the PKC activity in the uterine artery, 2) inhibits steroids-mediated downregulation of pressure-dependent myogenic tone in the uterine artery, and 3) whether chronic hypoxia has direct effects on the steroids-mediated responses in the uterine arteries. The results will provide exciting novel insights in biochemical, molecular, cellular, and pathophysiological adaptafion mechanisms involved in altering uteroplacental circulation in response to hypoxia in pregnancy, which has obvious clinical significance because the maladaptation of uterine circulation caused by chronic hypoxia in pregnancy is associated with fetal developmental abnormalities and maternal cardiovascular disorders.