HEMODYNAMIC REGULATION OF VASCULAR SMOOTH MUSCLE CELL

覆盖血管内表面的内皮细胞是 连续暴露于与血流相关的机械力， 它可以分解为两个分量;切应力， 作用于内皮细胞表面的摩擦力， 应变，垂直作用于血管壁。血液流动是一种 血管重塑重要决定因素， 裸露的血管，血流减少，易使动脉内膜化 增厚和动脉粥样硬化。流体剪应力和循环应变 调节内皮功能，刺激分泌的几个 来自内皮细胞的因子，包括一氧化氮（NO）、前列环素 （PGI 2）、转化生长因子（TGF β）、碱性成纤维细胞生长 因子（bGFG）、内皮素和血小板源性生长因子（PDGF）， 调节潜在的血管平滑肌细胞生长和功能。 这一建议的核心假设是，持续增加的离子 血流通过不同的方式调节底层平滑肌的生长 减少促有丝分裂素的释放，增加抗- 促有丝分裂物质。 第一个奖项申请建议定义急性和慢性 血流对内皮细胞功能的影响以及随后的 对底层平滑肌生长的影响。利用我们 新的灌注的跨毛细血管共培养系统， 血管平滑肌细胞可以同时长期暴露于 生理剪切应力和循环应变（脉动流），我们将 定义流动对以下方面的急性和慢性影响： （一）申请人 内皮释放抗有丝分裂物质（NO，PGI 2， TGF β）和促有丝分裂物质（PDGF、bFGF和内皮素）在共- 培养细胞 （二） 丝裂原活化蛋白激酶信号转导的内皮控制 (MAPK和p34/cdc 2）和在下面的血管平滑肌中的生长： NO、PGI 2和TGF β的作用。 (iii)丝裂原活化蛋白激酶信号（MAPK's和p34/cdc 2_ 和血管平滑肌细胞的生长， 细胞; TGF β、PDGF、bFGF和MMP的作用，s. 确定机械力对内皮细胞的作用是关键 平滑肌细胞生长的控制，因为血管内皮是 尽管在调节平滑肌细胞生长中起着关键作用， 因为流动对体内的几个方面有显著的影响， 内皮功能这些实验应该提供有价值的 信息中心，我们的理解的重要作用血流动力学 力在血管生物学中发挥作用，并因此进一步加深了我们对它的认识。 在心血管疾病病因学中的作用。

Endothelial cells covering the inner surface of blood vessels are continuously exposed to mechanical forces associated with blood flow, which can be resolved into two components; shear stress, a tangential frictional force which acts at the endothelial cell surface, and cyclic strain, acting perpendicular to the vascular wall. Blood flow is an important determinant of vascular remodeling in endothelial intact and denuded vessels with reduce flow predisposing arteries to intimal thickening and atherosclerosis. Fluid shear stress and cyclic strain modulate endothelial function by stimulating the secretion of several factors from endothelial cells including nitric oxide (NO), prostacyclin (PGI2), transforming growth factor (TGFbeta), basic fibroblast growth factor (bGFG), endothelin, and platelet-derived growth (PDGF) that can modulate the underlying vascular smooth muscle cell growth and function. The central hypothesis of this proposal is that sustained increased ion flow modulate the growth of the underlying smooth muscle by differentially decreasing the release of mitogenic and increasing the release of anti- mitogenic substances from endothelial cells. This First Award application proposes to define the acute and chronic effects of flow on endothelial cell function and the subsequent consequences on the growth of the underlying smooth muscle. Utilizing our novel perfused transcapillary co-culture system, whereby endothelial and vascular smooth muscle cells can be simultaneously chronically exposed to physiological shear stress and cyclic strain (pulsatile flow), we will define the acute and chronic effects of flow on: (i) endothelial release of anti-mitogenic substances (NO, PGI2, and TGFbeta) and mitogenic substances (PDGF, bFGF and endothelin) in co- cultured cells (ii) endothelial control of mitogen-activated protein kinase signaling (MAPK's and p34/cdc2) and growth in the underlying vascular smooth muscle: the role of NO, PGI2 and TGFbeta. (iii) mitogen activated protein kinase signaling (MAPK's and p34/cdc2_ and growth in vascular smooth muscle cells in the absence of endothelial cells; the role of TGFbeta, PDGF, bFGF and MMP,s. It is critical to define the role of mechanical force on endothelial control of smooth muscle cell growth because the vascular endothelium is though to play a pivotal role in regulating smooth muscle cell growth in vivo and because flow has significant effect on several aspects of endothelial function. These experiments should provide valuable information central to our understanding of the important role hemodynamic forces play in vascular biology,a nd thus further our knowledge of its role in the etiology of cardiovascular disease.