Endothelial Deformation and Coronary Arteriolar Function

描述（由申请人提供）：这是一项调查 心脏压迫对大鼠主动脉内皮细胞血管活性功能的影响 冠状小动脉和内皮细胞的机制 变形诱导的NO释放。 小动脉持续暴露于由心脏引起的节律性压迫， 收缩，这可能会影响其功能。我的假设是内皮细胞 冠状小动脉细胞对细胞变形敏感， 反应释放NO以通过扩张血管恢复其原始形状。 这一假设将在大鼠中在三个后续水平进行测试：灌注 心脏、离体冠状动脉和培养的冠状动脉内皮细胞 小动脉在离体和灌注心脏的特异性目标1中，我的目的是检查 心脏按压的频率和幅度之间的关系， 冠状动脉血流我将研究NO在心脏按压诱导的 增加冠状动脉流量，并将结果与 流量或肌源性诱导的流量增加。在《目标2》中，我计划 血管压迫对离体冠状动脉直径的影响 小动脉，对NO的释放，以及对肌源性反应和流动诱导的 膨胀在具体目标3中，在培养的内皮细胞中，我的目标是监测 [Ca ~（2+）]I和NO释放的变化 压缩引起的变形，并阐明之间的相关性 [Ca2最后，在具体目标4中，我计划 研究可能的信号转导途径， 内皮变形诱导的NO释放。 钾通道、细胞骨架和细胞膜小窝等。我相信 这些研究揭示的结果将证明一种新的生理学 控制机制，即心脏收缩，通过减少小动脉 直径，从而改变内皮细胞的形状， 一氧化氮，然后参与调节冠状动脉血流量。

DESCRIPTION (provided by applicant): This is a proposal to investigate the effects of cardiac compression on the vasoactive function of the endothelium of coronary arterioles and the mechanisms underlying the endothelial deformation-induced release of NO. The endothelium of intramural coronary arterioles is constantly exposed to rhythmic compression induced by cardiac contraction, which may affect its function. My hypothesis is that endothelial cells of coronary arterioles are sensitive to cellular deformation and in response release NO to restore their original shape by dilating the vessels. This hypothesis will be tested in rats at three subsequent levels: perfused hearts, isolated coronary arterioles and cultured endothelial cells of coronary arterioles. In Specific Aim 1 in isolated and perfused heart, I aim to examine the relationship between the frequency and magnitude of cardiac compression and coronary flow. I will examine the role of NO in cardiac compression-induced increases in coronary flow and contrast the results with those obtained by flow- or myogenically-induced increases in flow. In Specific Aim 2, I plan to study the effects of vascular compression on the diameter of isolated coronary arterioles, on the release of NO, and on the myogenic response and flow-induced dilation. In Specific Aim 3, in cultured endothelial cells, I aim to monitor the changes in [Ca2+]I and the release of NO in response to endothelial deformation induced by compression, and to elucidate the correlation between [Ca2+]I and the increases in Cytosolic NO. Finally, in Specific Aim 4, I plan to investigate the possible signal transduction pathways involved in endothelial deformation-induced release of NO. The specific role of endothelial potassium channels, cytoskeleton and caveolae will be studied. I believe that the findings revealed by these studies will demonstrate a new physiologic control mechanism, namely, that cardiac contractions, by reducing arteriolar diameter and hence changing the shape of endothelial cells enhance the release of NO, which then participates in the regulation of coronary blood flow.