VASCULAR RESPONSE TO ALTERATION IN HEMODYNAMIC FLOW

血管对血流变化的反应

• 批准号: 6390753
• 负责人: SHUNICHIRO S OKADA
• 金额: $ 25.15万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-08-06 至 2003-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6390753
• 关键词: blood vessel transplantation; capillary; cell growth regulation; cell migration; coronary bypass; gene expression; gene targeting; genetically modified animals; hemodynamics; human tissue; hyperplasia; in situ hybridization; laboratory mouse; messenger RNA; mixed tissue /cell culture; muscle cells; mutant; plasminogen activator; plasminogen activator inhibitors; vascular endothelium; vascular smooth muscle; veins

DESCRIPTION (Adapted from Applicant's Abstract): Saphenous vein graft (SV.G) neointimal thickening post coronary artery bypass grafting (CABG) is an adaptive mechanism by the SVG to withstand the hemodynamic stress that results from the change in environment from the venous to the arterial circulation. However, this adaptive response often becomes pathologic resulting in focal narrowings or graft closure. In favorable outcomes, the intimal growth reaches a steady state where luminal area and functional integrity of the vein graft is maintained. In this setting, vessel wall homeostatsis may be maintained by the intact endothelium which exerts its regulatory influence on the process of neointimal thickening by production of soluble factors. Preliminary evidence suggests that one of the soluble factors may be plasminogen activator inhibitory (PAI-1) and its increase in expression appears to be flowmediated. PAI-1 has been shown to play a role in smooth muscle cell (SMC) migration and neointimal thickening. Specific hypothesis to be tested in this proposal is that enclothelial (EC) PAI-1 expression is one of the predominant mechanisms responsible for flow-mediated endothelial control of intimal changes in arterial conduits. In specific aim 1, using a perfused transcapillary co-culture in vitro system, we will determine if there is an EC influence on SIVIC migration in response to pulsatile flow. In specific aim 2, we will determine if pulsatile flow alters EC PAI-1 expression in the presence of SMC. In specific aim 3, to determine if flow-induced EC PAI-1 -expression is one of the predominant mechanisms behind endothelial influence on SMC migration, we will study the following combinations using mutant null mice technology: (i) the migratory behavior of murine wildtype SMC co-cultured with PAI-1 null EC and (ii) the effect of active PAI-1 repletion on the migratory behavior of wildtype SMC co-cultured with PAI-1 null EC. In specific Im 4, to determine if SMC PAI-1 is a co-participant in regulating the process of SMC migration, we will tudy the migratory behavior of PAI-1 null SIVIC co-cultured with wildtype EC. In specific aim 5, to etermine if SVG patency is associated with an altered expression of PAI-1 mRNA in vein graft luminal ndothelial cells, we will perform comparative analysis of PAI-1 expression in EC from patent SVG vs. occluded SVG using in situ hybridization. Identifying the factors that inhibit vein graft neointimal thickening will allow the development of target-directed pharmacological interventions to control this process.

描述（改编自申请人的摘要）：隐静脉移植（SV.G） 冠状动脉搭桥术后新内膜增厚（CABG）是 SVG的自适应机制承受了产生的血液动力学应力 从环境从静脉循环到动脉循环的变化。 但是，这种适应性反应通常会成为病理学，导致局灶性 狭窄或移植物闭合。在有利的结果中，内膜生长达到 静脉移植的腔面积和功能完整性为 维护。在这种情况下，可以通过 完整的内皮对其进行调节的影响 通过生产可溶性因子的新内膜增厚。初步证据 表明可溶性因子之一可能是纤溶酶原激活剂 抑制（PAI-1）及其表达的增加似乎被介导。 PAI-1已显示在平滑肌细胞（SMC）迁移中起作用 新膜增厚。在此提案中要检验的具体假设是 那个环层（EC）PAI-1表达是主要机制之一 负责流动介导的内皮控制的内膜变化 动脉导管。在特定的目标1中，使用灌注的毛细管 在体外系统中共培养，我们将确定EC是否对 响应脉动流动的西维克迁移。在特定的目标2中，我们将 确定在SMC存在下脉冲流是否改变EC PAI-1的表达。 在特定目标3中，确定流动诱导的EC PAI-1-表达是否是 内皮影响对SMC迁移的主要机制，我们 将使用突变零小鼠技术研究以下组合：（i） 鼠野生型SMC的迁徙行为与PAI-1 null EC共同培养 （ii）主动PAI-1补充对迁徙行为的影响 WildType SMC与PAI-1 NULL EC共同培养。在特定的IM 4中，确定是否 SMC PAI-1是调节SMC迁移过程的共同参与者，我们 会涉及pai-1 null sivic与野生型共培养的迁移行为 EC。在特定的目标5中，以确定是否与变化有关 PAI-1 mRNA在静脉移植腔腔片细胞中的表达，我们将 从专利SVG VS中对EC中的PAI-1表达进行比较分析。 使用原位杂交阻塞SVG。确定抑制的因素 静脉移植物新内膜增厚将允许发展目标定向 控制此过程的药理干预措施。