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）：剪切应力是由内皮表面的血流产生的摩擦力，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剪切应力在血管表型的变化中可能与心血管疾病有关。长期升高的剪切应力刺激动脉生长并增加管腔大小。通常，这种向外的重塑一直持续到将剪切应力恢复到基线为止，从而提供了重要的稳态机制。这种反应有助于正常发育，对生长动脉粥样硬化斑块（Glagov现象）的补偿性反应以及附带的发展。实验研究表明，升高的剪切应力在内皮细胞中激活PIS激酶/AKT系统，从而导致内皮一氧化氮合酶（ENOS）（ENOS）（ENOS）以及动脉壁的生长和重塑。尽管具有潜在的临床相关性，但很少有研究将这些实验发现转化为人类。我们的初步数据表明，用作旁路导管的径向动脉去除尺骨动脉流量显着增加，因为它可以容纳所需的血液供应。在接下来的八周内，这种流动增加与个人之间的重塑反应有关。我们建议研究这种重塑响应的局部和系统决定因素。在AIM 1中。我们将表征尺纳尔动脉几何形状的变化以及人类剪切应力的慢性增加所产生的功能。在AIM 2中。我们将将基线时测量的局部和系统因素联系起来，以向外重塑反应的尺骨动脉。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。我们还将研究径向动脉分离的片段中的特定信号通路。在AIM 3中，我们将完成干预研究，以探测潜在的机制（衍生内皮的NO和线粒体功能障碍）可能会导致冠状动脉疾病患者向外重塑的受损。该建议利用了独特的临床状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管理有关的重要新信息。