Endothelial Deformation and Coronary Arteriolar Function

描述(由申请人提供)：这是一份调查 心脏压迫对血管内皮细胞血管活性功能的影响 冠状小动脉与内皮细胞的作用机制 形变诱导NO的释放。冠状动脉壁内皮细胞 小动脉经常受到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 冠状小动脉的细胞对细胞变形很敏感 反应释放NO，通过扩张血管恢复原来的形状。 这一假设将在随后的三个水平上在大鼠身上进行测试：灌流 心脏、离体冠状小动脉和培养的冠状动脉内皮细胞 小动脉。在特定目标1中，在隔离和灌流的心脏中，我的目标是检查 心脏受压的频率和幅度与心脏功能的关系 冠脉血流。我将研究一氧化氮在心脏压迫中的作用。 冠状动脉流量的增加，并将结果与通过 血流或生肌引起的血流增加。在具体目标2中，我计划 血管压迫对离体冠脉直径影响的研究 小动脉对NO释放的影响以及对肌源性反应和血流诱导的影响 扩张。在具体目标3中，在培养的内皮细胞中，我的目标是监控 血管内皮细胞内钙离子浓度的变化与一氧化氮的释放 压缩引起的变形，并阐明两者之间的相关性 [CA2]i和胞浆NO含量的增加。最后，在具体目标4中，我计划 为了研究可能涉及的信号转导途径 内皮变形诱导NO的释放。内皮细胞的特殊作用 将对钾通道、细胞骨架和小窝进行研究。我相信 这些研究揭示的发现将展示一种新的生理学 控制机制，即心脏收缩，通过减少微动脉 直径，从而改变内皮细胞的形状，促进了释放 NO参与冠脉血流量的调节。

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.