Determinants of Shear Stress-Mediated Arterial Remodeling

描述(申请人提供)：剪切力是血流在内皮表面产生的摩擦力，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有关，但低水平和高水平的切应力都会导致血管表型的变化，这可能与心血管疾病有关。长期升高的切应力刺激动脉生长并增加管腔大小。一般来说，这种向外的重塑一直持续到切应力恢复到基线，从而提供了一个重要的动态平衡机制。这种反应有助于正常发育，对不断增长的动脉粥样硬化斑块(GLAGOV现象)的代偿反应，以及侧枝循环的发展。实验研究表明，剪切力升高会激活内皮细胞中的PIS/Akt系统，导致内皮型一氧化氮合酶(ENOS)的激活和表达增加，从而导致动脉壁的生长和重塑。尽管它们具有潜在的临床相关性，但很少有研究将这些实验结果转化为人类。我们的初步数据显示，切除桡动脉作为旁路管道，可以显著增加尺动脉的血流量，因为它可以容纳手部所需的血液供应。这种血流增加与接下来的八周内的重塑反应有关，不同的人有不同的反应。我们建议研究这种重塑反应的局部和系统决定因素。在目标1中，我们将描述由人体慢性剪应力增加引起的尺动脉形态和功能的变化。在目标2中，我们将把基线测量的局部和系统因素与尺动脉外向重塑反应联系起来。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。我们还将研究分离的桡动脉节段中的特定信号通路。在目标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和线粒体的丢失！功能障碍)，这可能是冠状动脉疾病患者外向重塑受损的原因。这项建议利用一种独特的临床情况来研究人类的外向重构，我们认为这些研究将产生与血管疾病患者的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.