ENDOTHELIAL DEPENDENCE OF MICROCIRCULATORY REGULATION

微循环调节的内皮依赖性

• 批准号: 6272869
• 负责人: Gabor Kaley
• 金额: $ 38.07万
• 依托单位: NEW YORK MEDICAL COLLEGE
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-07-01 至 1999-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6272869
• 关键词: animal tissue; calcium flux; cardiovascular pharmacology; enzyme activity; exercise; free radicals; heart failure; hemodynamics; human tissue; laboratory rat; microcirculation; muscle metabolism; nitric oxide; nitric oxide synthase; oxygen consumption; prostaglandins; protein tyrosine kinase; superoxide dismutase; vascular endothelium; vascular resistance; vasodilators; vasomotion; video microscopy

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.

拟议的工作是基于项目负责人以前的研究， 与本计划项目的联系和初步数据， 血管活性、内皮源性介质在血管内皮细胞中的作用， 微血管功能的调节。 我们计划继续检查 内皮源性一氧化氮的特殊作用， 和氧自由基物种在血管反应性，以及在剪切 应力和压力诱导的微血管张力变化，在体内和体内 体外 在具体目标1的背景下，我们将检验以下假设： 信号转导通路参与了 通过微血管内皮细胞的剪切力， 一氧化氮和胰头素的释放与酪氨酸激酶有关 内皮细胞活性、细胞骨架结构和钾通道 细胞 我们还计划研究诱导ecNOS的时间过程 微血管中的活性响应于剪切应力的增加。 在 具体目标2我们将继续研究运动的效果 训练对大鼠微血管内皮细胞功能的影响。 我们将测试 血流（剪切应力）间歇性增加的假设 在运动活动期间， ecNOS、考克斯-1和SOD的活性，而一氧化氮的可用性增加 会影响骨骼肌的氧代谢，所有这些都会倾向于 促进血液流动和工作效率的增加运动训练 骨骼肌 在具体目标3中，内皮对 将研究心力衰竭引起的小动脉功能变化 犬冠状动脉和骨骼肌血管以及冠状动脉微血管 人类 我们将检验心力衰竭与 内皮合成和/或活性严重降低， 微血管的一氧化氮和扩张素， 导致循环衰竭 在所有三个目标中， 激动剂，流量和压力将在隔离，灌注 在受控条件下和在某些情况下在体内， 已确立的方法，包括通过电视测量直径 显微镜 血管灌注液中的一氧化氮将以NO（2）的形式进行测定， 血浆中为NO（3）; cNOS、考克斯-1和SOD基因表达和酶 水平将通过分子生物学技术定量， 免疫组化