FETAL HYPOXEMIA AND ENDOTHELIUM DERIVED NITRIC OXIDE

点击翻译按钮获取中文摘要

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.