FETAL HYPOXEMIA AND ENDOTHELIUM DERIVED NITRIC OXIDE

低氧血症是胎儿发病和死亡的主要原因之一。 胎儿血管再分布的血管机制 对低氧血症期间的心输出量了解甚少。 我们建议 慢性低氧血症改变内皮细胞一氧化氮基因表达 突触（eNOS）和诱导型NOS（iNOS）和血管反应性， 对氧合减少的适应性反应。 我们的初步数据 显示长期低氧血症增加胎儿心脏和减少胎儿 前脑eNOS mRNA表达。 此外，低氧血症4天抑制 胎儿颈动脉的内皮依赖性舒张， 7天后逆转。 因此，胎儿低氧血症既影响NOS基因， 以器官特异性方式表达和NO介导的 离体胎儿动脉一氧化氮在介导血管紧张素转换酶活性中的作用 对慢性低氧血症的适应将在暴露于 在以下目标中，12%的O2持续4、7或14天。 目标1：测试 长期低氧血症改变eNOS基因表达的假说 和血管中iNOS mRNA的表达。靶mRNA 将在胎儿脑、心脏和肺中检测和定量， 以及颈动脉和肺动脉通过核糖核酸酶保护 比色法 目的2：验证长期低氧血症 减弱离体胎儿肺动脉和颈动脉的扩张反应 通过抑制eNOS mRNA表达和内皮源性NO 生产 目的3：验证长期低氧血症 抑制离体胎儿脑动脉的舒张。 的影响 慢性低氧血症对激动剂刺激的舒张、氧敏感性的影响 胎儿血管内皮细胞，血流刺激的舒张将 在视频显微镜装置上在分离的脑动脉中测量。 目的4：检验长期低氧血症增加扩张器 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 NO是胎儿缺氧应激的适应性反应。

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.