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: 6183035
• 负责人: LOREN P THOMPSON
• 金额: $ 22.13万
• 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 2002-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6183035
• 关键词: RNase protection assay; brain; carotid artery; cerebral artery; embryo /fetus hypoxia; gene expression; guinea pigs; heart circulation; immunocytochemistry; lung; messenger RNA; microcirculation; molecular cloning; nitric oxide; nitric oxide synthase; nucleic acid probes; oxygen tension; pulmonary artery; solution hybridization; statistics /biometry; vascular endothelium; vascular resistance; vasoconstriction; vasodilation; video microscopy

Hypoxemia is one of the leading causes of fetal morbidity and mortality. The vascular mechanisms responsible for the redistribution of fetal cardiac output during hypoxemia are poorly understood. We propose that chronic hypoxemia alters gene expression of endothelial nitric oxide synapse (eNOS) and inducible NOS (iNOS) and vascular reactivity as adaptive responses to the reduced oxygenation. Our preliminary data show that prolonged hypoxemia increases fetal heart and decreases fetal forebrain eNOS mRNA expression. Further, hypoxemia for 4 days inhibits the endothelium-dependent relaxation of the fetal carotid artery but is reversed after 7 days. Thus, fetal hypoxemia affects both NOS gene expression in an organ specific manner and NO-mediated relaxation of isolated fetal arteries. The role of NO in mediating the vascular adaptations to chronic hypoxemia will be studied in fetuses exposed to 12 percent O2 for 4,7,or 14 days in the following aims. Aim 1: To test the hypothesis that prolonged hypoxemia alters gene expression of eNOS and iNOS mRNA in both fetal guinea pig organs and arteries. Target mRNA will be detected and quantified in the fetal brain, heart, and lung as well as carotid and pulmonary arteries by a ribonuclease protection assay. Aim 2: To test the hypothesis that prolonged hypoxemia attenuates dilator responses of isolated fetal pulmonary and carotid arteries by inhibiting eNOS mRNA expression and endothelium-derived NO production. Aim 3: To test the hypothesis that prolonged hypoxemia inhibits relaxation of isolated fetal cerebral arteries. The effect of chronic hypoxemia on agonist-stimulated relaxation, oxygen sensitivity of the fetal vascular endothelium, and flow-stimulated relaxation will be measured in isolated cerebral arteries on a video microscopy setup. Aim 4: To test the hypothesis that prolonged hypoxemia increases dilator responses of the fetal coronary microcirculation. Thus, this proposal will identify the role of NOS gene expression and endothelium-derived NO as adaptive responses to fetal hypoxic stress.

低氧血症是胎儿发病和死亡的主要原因之一。 负责胎儿重新分布的血管机制 低氧血症期间的心输出量知之甚少。 我们建议 慢性低氧血症改变内皮一氧化氮基因表达 突触 (eNOS) 和诱导型 NOS (iNOS) 以及血管反应性 对氧合减少的适应性反应。 我们的初步数据 表明长期低氧血症会增加胎儿心脏并降低胎儿 前脑 eNOS mRNA 表达。 此外，持续 4 天的低氧血症会抑制 胎儿颈动脉的内皮依赖性松弛，但 7天后逆转。 因此，胎儿低氧血症影响 NOS 基因 以器官特异性方式表达和 NO 介导的松弛 分离胎儿动脉。 NO 在介导血管生成中的作用 将研究暴露于以下环境的胎儿对慢性低氧血症的适应情况 12% O2 持续 4,7 或 14 天以实现以下目标。 目标 1：测试 长期低氧血症会改变 eNOS 基因表达的假设 和 iNOS mRNA 在胎儿豚鼠器官和动脉中的表达。靶标mRNA 将在胎儿大脑、心脏和肺中被检测和量化 以及颈动脉和肺动脉受核糖核酸酶保护 化验。 目标 2：检验长期低氧血症的假设 减弱离体胎儿肺动脉和颈动脉的扩张器反应 通过抑制 eNOS mRNA 表达和内皮源性 NO 生产。 目标 3：检验长期低氧血症的假设 抑制离体胎儿脑动脉的松弛。 的效果 激动剂刺激放松、氧敏感性导致的慢性低氧血症 胎儿血管内皮细胞和血流刺激的松弛将 在视频显微镜装置上测量孤立的脑动脉。 目标 4：检验长期低氧血症会增加扩张器的假设 胎儿冠状动脉微循环的反应。 因此，本提案 将确定 NOS 基因表达和内皮源性的作用 NO 作为对胎儿缺氧应激的适应性反应。