ENDOTHELIAL DEPENDENCE OF MICROCIRCULATORY REGULATION

建议的工作是基于项目负责人以前在 与此计划项目的联系和已通过 血管活性、内皮源性介质在血管内皮细胞损伤中的作用 微血管功能的调节。我们计划继续考试。 内皮源性一氧化氮、前列腺素的具体作用 以及氧自由基在血管反应性和剪切性中的作用 应激和压力引起的微血管张力的变化，体内和 体外培养。在具体目标1的背景下，我们将检验假设 参与转导的信号转导途径 通过微血管内皮细胞的剪切力导致 一氧化氮和前列腺素的释放与酪氨酸激酶有关 内皮细胞活性、细胞骨架结构与钾通道 细胞。我们还计划研究ecNOS诱导的时间进程。 微血管的活性对剪应力的增加作出反应。在……里面 具体目标2我们将继续研究锻炼的效果 对大鼠微血管内皮细胞功能的训练。我们将测试 血流间歇性增加(切应力)的假设 在运动期间的活动将导致上调 一氧化氮合酶、环氧合酶-1和超氧化物歧化酶，以及一氧化氮的增加 会影响骨骼肌氧代谢，所有这些都会倾向于 促进运动训练后血流量和工作效率的增加 骨骼肌。在特定目标3中，内皮细胞对 将调查心力衰竭引起的微动脉功能的变化。 犬冠状动脉和骨骼肌血管及冠脉微血管 人类的生命。我们将检验心力衰竭与 血管内皮细胞合成和/或活性严重降低 一氧化氮和扩张剂前列腺素的微血管 缺陷会导致循环衰竭。在所有三个AIMS的回应中 对于激动剂，流量和压力将在隔离、灌流中进行研究 微动脉在受控条件下，在某些情况下，在体内，通过 既定的方法，包括通过电视测量直径 显微镜。血管灌流液中的一氧化氮将被检测为NO(2)， 血浆中NO(3)、cNOS、COX-1和SOD基因表达及酶活性 水平将通过分子生物学技术和 免疫组织化学。

The work proposed is based on the Project Leader's previous studies in connection with this Program Project and preliminary data that have been obtained on the role of vasoactive, endothelium-derived mediators in the regulation of microvascular function. We plan to continue the examination of the specific roles of endothelium-derived nitric oxide, prostaglandins and oxygen radical species in vascular reactivity, as well as in shear stress and pressure-induced changes in microvascular tone, in vivo and in vitro. In the context of Specific Aim 1 we will test the hypothesis that the signal transduction pathway that is involved in the transmission of shear forces through microvascular endothelial cells to result in the release of nitric oxide and prostaglandins is related to tyrosine kinase activity, cytoskeletal structures and potassium channels in endothelial cells. We also plan to study the time course of the induction of ecNOS activity in microvessels in response to increases in shear stress. In Specific Aim 2 we will continue our studies of the effects of exercise training on microvascular endothelial cell function in rats. We will test the hypothesis that intermittent increases in blood flow (shear stress) during episodes of exercise activity will result in the upregulation of ecNOS, COX-1 and SOD, and that the increased availability of nitric oxide will affect skeletal muscle oxygen metabolism, all of which will tend to promote increases in blood flow in and work efficiency of exercise-trained skeletal muscle. In Specific Aim 3 the endothelial contribution to changes in arteriolar function due to heart failure will be investigated in coronary and skeletal muscle vessels of dogs and coronary microvessels of humans. We will test the hypothesis that heart failure is associated with a severe reduction in the endothelial synthesis/and or activity in microvessels of both nitric oxide and dilator prostaglandins and that this defect contributes to circulatory collapse. In all three aims responses to agonists, flow and pressure will be studied in isolated, perfused arterioles under controlled conditions and in some instances in vivo, by established methods, including diameter measurements by television microscopy. Nitric oxide will be assayed in vessel perfusates as NO(2), and in plasma as NO(3); cNOS, COX-1 and SOD gene expression and enzyme levels will be quantified by molecular biology techniques and immunohistochemistry.