Determinants of Shear Stress-Mediated Arterial Remodeling

剪应力介导的动脉重塑的决定因素

• 批准号: 7452358
• 负责人: Joseph A. Vita
• 金额: $ 47.74万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7452358
• 关键词: Accounting; Acetylcarnitine; Arterial Fatty Streak; Arteries; Ascorbic Acid; Atherosclerosis; Biological Availability; Biological Markers; Biology; Biometry; Blood Vessels; Blood flow; Boston; Bypass; Caliber; Cardiovascular Diseases; Cardiovascular system; Chronic; Clinical; Contralateral; Coronary Arteriosclerosis; Data; Data Analyses; Development; Diabetes Mellitus; Dimensions; Disease; Dyslipidemias; Endothelial Cells; Endothelium; Excision; Functional disorder; Growth; Hand; Harvest; Health; Human; Immunohistochemistry; In Vitro; Individual; Inflammatory; Intervention Studies; Invasive; Matrix Metalloproteinases; Measurement; Measures; Mediating; Mitochondria; Nitric Oxide; Operative Surgical Procedures; Organ; Oxidants; Pathologist; Patients; Pattern; Phenotype; Phosphotransferases; Physiological; Physiology; Process; Research Design; Research Personnel; Risk Factors; Schools; Signal Pathway; Signal Transduction; Stem cells; Structure; Structure of ulnar artery; Surface; Surgeon; System; Thioctic Acid; Transactivation; Translating; Trees; Ultrasonography; Universities; Vascular Diseases; Vascular Endothelial Growth Factor Receptor; Vascular blood supply; Vascular remodeling; Vasodilator Agents; Week; arterial remodeling; clinically relevant; human NOS3 protein; improved; programs; radial artery; radius bone structure; research study; response; shear stress; size; translational study

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.

描述（由申请人提供）：剪切应力是血液在内皮表面流动产生的摩擦力，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可能与心血管疾病相关的血管表型变化。长期升高的剪切应力会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，从而提供了重要的稳态机制。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（格拉戈夫现象）以及侧枝发育。实验研究表明，升高的剪切应力会激活内皮细胞中的 PIS 激酶/Akt 系统，从而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。我们的初步数据表明，切除桡动脉作为旁路导管会显着增加尺动脉流量，因为它可以满足手部所需的血液供应。这种流量的增加与接下来八周内的重塑反应有关，而重塑反应因人而异。我们建议调查这种重塑反应的局部和系统决定因素。在目标 1 中，我们将描述人类剪切应力长期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孤立部分的特定信号传导途径。在目标 3 中，我们将完成干预研究，以探讨可能导致冠状动脉疾病患者外向重塑受损的潜在机制（内皮源性 NO 的丢失和线粒体！功能障碍）。该提案利用独特的临床情况来研究人类的外向重塑，我们建议这些研究将产生与血管疾病患者的治疗相关的重要新信息。