Fetal Hypoxemia and endothelium derived nitric oxide

胎儿低氧血症和内皮源性一氧化氮

• 批准号: 6623792
• 负责人: LOREN P THOMPSON
• 金额: $ 25.99万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-05-01 至 2006-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6623792
• 关键词: acetylcholine; blood flow measurement; bradykinin; cardiac myocytes; coronary vessels; embryo /fetus hypoxia; gene expression; guinea pigs; heart circulation; hemodynamics; immunocytochemistry; in situ hybridization; laser capture microdissection; messenger RNA; microcirculation; nitric oxide; nitric oxide synthase; polymerase chain reaction; prostaglandins; vascular endothelium

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.

描述：（由申请人提供）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 在心脏低氧血症期间，适应性机制较差 明白了。我们假设胎儿​​低氧血症改变了 血管中的氧敏感基因，例如一氧化氮合酶（NOS） 内皮细胞并改变冠状动脉血流的调节。我们建议 慢性低氧血症是启动氧敏感细胞编程的刺激因素 改变胎儿冠状动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编程导致持续的机制 出生后心血管功能的变化。胎儿低氧血症是由 将怀孕的豚鼠置于低氧室（12%O2）中 14 天。 冠状动脉对激动剂刺激的反应性是在隔离的情况下测量的 来自常氧和低氧动物的灌注胎儿心脏。基因表达和 eNOS/iNOS 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测定 杂交。单个细胞的激光捕获显微切割将 应用于心脏切片以测量细胞特异性 NOS mRNA。测试 改变的胎儿反应是否在出生后持续存在，冠状动脉 将在青少年心脏中研究反应和 NOS 基因表达 先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状动脉的NO依赖性机制 微循环。目标 2：测试慢性低氧血症是否会增加 eNOS 和 胎儿内皮、血管和心肌细胞中 iNOS 基因的表达 心。目标 3：测试慢性低氧血症是否会永久改变冠状动脉 出生后动脉血流反应作为胎儿编程的机制。这 该提案将提供有关慢性低氧血症如何影响的新信息 胎儿冠状动脉血流调节中的内皮依赖性机制 帮助我们了解冠状循环如何适应慢性疾病 子宫内和产后低氧血症。