Fetal Hypoxemia and endothelium derived nitric oxide

描述：(申请人提供)慢性低氧血症是导致 胎儿发病率和死亡率。胎儿重新分配其心输出量 在低氧血症期间通过不佳的适应机制进入心脏 明白了。我们假设胎儿低氧血症改变了血管内皮生长因子的表达 血管中的一氧化氮合酶(NOS)等氧敏感基因 血管内皮细胞并改变冠脉血流的调节。我们建议 慢性低氧血症是启动氧敏感程序的刺激 改变胎儿冠脉反应性和血流调节的基因。 胎儿期氧敏感基因表达的永久性变化 低氧血症可能是胎儿程序化导致持续的一种机制 出生后心血管功能的变化。胎儿低氧血症由以下因素引起 将怀孕的豚鼠置于低氧舱(12%O2)中14天。 冠状动脉对激动剂刺激的反应性在 来自常氧和低氧动物的灌流胎儿心脏。基因表达和 内皮型一氧化氮合酶/诱导型一氧化氮合酶在内皮、血管平滑肌和心脏中的分布 细胞将通过免疫细胞化学和非放射性原位检测 杂交。激光捕获单个细胞的显微解剖将 应用于心脏切片，用于细胞特异性一氧化氮合酶基因的测定。为了测试 改变的胎儿反应是否在出生后持续，冠状动脉 将研究青少年心脏的反应和一氧化氮合酶基因的表达 以前在子宫内暴露于低氧血症的动物。目标1：检验假设 慢性低氧血症改变胎儿冠脉一氧化氮依赖机制 微循环。目的2：检测慢性低氧血症是否会增加eNOS和eNOS INOS基因在胎儿内皮细胞、血管细胞和心脏细胞中的表达 心。目的3：测试慢性低氧血症是否会永久性地改变冠状动脉 出生后动脉血流反应作为胎儿程序化的一种机制。这 该提案将提供关于慢性低氧血症如何影响的新信息 血管内皮细胞依赖机制在胎儿冠脉血流调节中的作用 有助于我们理解冠脉循环如何适应慢性 宫内和产后低氧血症。

DESCRIPTION: (Provided By Applicant) Chronic hypoxemia is a leading cause of fetal morbidity and mortality. The fetus redistributes its cardiac output during hypoxemia to the heart by adaptive mechanisms that are poorly understood. We hypothesize that fetal hypoxemia alters the expression of oxygen-sensitive genes such as nitric oxide synthase (NOS) in the vascular endothelium and alters the regulation of coronary blood flow. We propose that chronic hypoxemia is a stimulus for initiating programming of oxygen-sensitive genes that alters coronary reactivity and flow regulation in the fetus. Permanent changes in the expression of oxygen-sensitive genes during fetal hypoxemia may be a mechanism by which fetal programming causes sustained changes in cardiovascular function after birth. Fetal hypoxemia is induced by placing pregnant guinea pigs in a hypoxic chamber (12 percentO2) for 14 days. Coronary artery reactivity to agonist stimulation is measured in isolated perfused fetal hearts from normoxic and hypoxemic animals. Gene expression and distribution of eNOS/iNOS in endothelial, vascular smooth muscle, and cardiac cells will be determined by immunocytochemistry and nonradioactive in situ hybridization. Laser Capture Microdissection of individual cells will be applied to heart sections for measure of cell specific NOS mRNA. To test whether altered fetal responses are sustained postnatally, coronary artery responses and NOS gene expression will be studied in hearts from adolescent animals previously exposed to hypoxemia in utero. Aim 1: To test the hypothesis that chronic hypoxemia alters NO-dependent mechanisms of the fetal coronary microcirculation. Aim 2: To test whether chronic hypoxemia increases eNOS and iNOS gene expression in endothelial, vascular and cardiac cells of the fetal heart. Aim 3: To test whether chronic hypoxemia permanently alters coronary artery flow responses after birth as a mechanism of fetal programming. This proposal will provide novel information on how chronic hypoxemia affects endothelial-dependent mechanisms in the regulation of fetal coronary flow and aid in our understanding of how the coronary circulation adapts to chronic hypoxemia in utero and postnatally.