Determinants of Shear Stress-Mediated Arterial Remodeling

描述（由申请人提供）：剪切应力是血液在内皮表面流动时产生的摩擦力，是动脉结构和生物学的关键决定因素。虽然生理水平与动脉健康相关，但低水平和高水平的剪切应力都会产生血管表型的变化，这可能与心血管疾病有关。长期升高的剪应力刺激动脉生长，增加管腔大小。一般来说，这种向外重塑会持续到剪应力恢复到基线，从而提供了一个重要的内稳态机制。这种反应有助于正常发育、对动脉粥样硬化斑块生长的代偿反应（Glagov现象）和侧枝发育。实验研究表明，升高的剪切应力激活内皮细胞的PIS激酶/Akt系统，导致内皮型一氧化氮合酶（eNOS）的激活和表达增加，促进动脉壁的生长和重塑。尽管它们具有潜在的临床意义，但很少有研究将这些实验结果转化为人类。我们的初步数据表明，切除桡动脉作为旁路导管可以显著增加尺动脉的流量，因为它可以满足手部所需的血液供应。在接下来的八周内，血流的增加与个体的重塑反应有关。我们建议研究这种重塑反应的局部和全身决定因素。在目标1中。我们将描述尺动脉几何形状和功能的变化所产生的慢性增加的剪切应力在人类。在目标2中。我们将把基线测量的局部和全身因素与尺动脉外展重塑反应联系起来。在这方面，我们将评估系统性危险因素、基质金属蛋白酶、循环内皮祖细胞和血管功能的非侵入性测量。我们还将研究桡动脉分离段的特定信号通路。在Aim 3中，我们将完成干预研究，以探索潜在的机制（内皮来源的NO和线粒体的损失）！功能障碍)可能解释冠状动脉疾病患者的外重构受损。该建议利用独特的临床情况来研究人类的外重构，我们认为这些研究将产生与血管疾病患者管理相关的重要新信息。

DESCRIPTION (provided by applicant): Shear stress is the frictional force produced by the flow of blood at the endothelial surface and is a critical determinant of arterial structure and biology. While physiological levels are associated with arterial health, both low and high levels of shear stress produce changes in vascular phenotype that may be relevant to cardiovascular disease. Chronically elevated shear stress stimulates arterial growth and increases lumen size. In general, this outward remodeling continues until shear stress is restored to baseline, thus providing an important homeostatic mechanism. This response contributes to normal development, the compensatory response to growing atherosclerotic plaques (Glagov Phenomenon), and collateral development. Experimental studies have shown that elevated shear stress activates the PIS kinase/Akt system in endothelial cells leading to activation and increased expression of endothelial nitric oxide synthase (eNOS) and growth and remodeling of the arterial wall. Despite their potential clinical relevance, few studies have translated these experimental findings to humans. Our preliminary data show that removal of the radial artery for use as a bypass conduit produces a marked increase in ulnar artery flow as it accommodates the required supply of blood to the hand. This flow increase is associated with a remodeling response over the next eight weeks that varies among individuals. We propose to investigate local and systemic determinants of this remodeling response. In Aim 1. we will characterize the changes in ulnar artery geometry and function produced by a chronic increase in shear stress in humans. In Aim 2. we will relate local and systemic factors measured at baseline to outward remodeling response of the ulnar artery. In this regard, we will assess systemic risk factors, matrix metalloproteinases, circulating endothelial progenitor cells, and non-invasive measures of vascular function. We will also investigate specific signaling pathways in isolated segments of radial artery. In Aim 3, we will complete intervention studies to probe potential mechanisms (loss of endothelium-derived NO and mitochondria! dysfunction) that may account for impaired outward remodeling in patients with coronary artery disease. This proposal takes advantage of a unique clinical situation to study outward remodeling in humans, and we suggest that these studies will yield important new information that is relevant to the management of patients with vascular disease.