Determinants of Shear Stress-Mediated Arterial Remodeling

描述（由申请人提供）：剪切应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相关，但低水平和高水平的剪切应力都会引起可能与心血管疾病相关的血管表型变化。慢性升高的剪切应力刺激动脉生长并增加管腔尺寸。一般来说，这种向外重塑持续到剪切应力恢复到基线，从而提供了一个重要的稳态机制。这种反应有助于正常发育、对生长的动脉粥样硬化斑块的代偿反应（Glagov现象）和侧支发育。实验研究表明，升高的剪切应力激活内皮细胞中的PIS激酶/Akt系统，导致内皮一氧化氮合酶（eNOS）的激活和表达增加以及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。我们的初步数据显示，去除桡动脉作为旁路导管可显著增加尺动脉血流，因为它可适应手部所需的血液供应。这种流量增加与未来八周的重塑反应有关，这在个体之间有所不同。我们建议调查这种重塑反应的局部和全身决定因素。在目标1中。我们将描述由人类剪切应力的慢性增加所产生的尺动脉几何形状和功能的变化。在目标2中。我们将把在基线测量的局部和全身因素与尺动脉的向外重塑反应联系起来。在这方面，我们将评估系统性风险因素，基质金属蛋白酶，循环内皮祖细胞，和血管功能的非侵入性措施。我们也将研究特定的信号通路在孤立的桡动脉段。在目标3中，我们将完成干预研究，以探索潜在的机制（内皮源性NO和线粒体的损失！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。这项建议利用了一个独特的临床情况，研究在人类的外向重塑，我们认为，这些研究将产生重要的新信息，是相关的血管疾病患者的管理。

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.