CELLULAR MECHANISMS OF VASCULAR GRAFT FAILURE

血管移植失败的细胞机制

• 批准号: 2218304
• 负责人: ALLAN D. CALLOW
• 金额: $ 25.34万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 1990
• 资助国家: 美国
• 起止时间: 1990-08-01 至 1996-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2218304
• 关键词: artery stenosis; cardiovascular disorder prevention; cardiovascular pharmacology; cell migration; chemoprevention; dosage; extracellular matrix proteins; gene induction /repression; growth factor receptors; in situ hybridization; integrins; laboratory rabbit; muscle cells; nonhuman therapy evaluation; northern blottings; platelet derived growth factor; protein sequence; receptor expression; tissue /cell culture; transforming growth factors; vascular smooth muscle; vitronectin

As a leading cause of restenosis, neointimal hyperplasia is common to small caliber grafting, endarterectomy and balloon angioplasty. Following surgical injury to the arterial wall, activated smooth muscle cells (SMC) migrate and then proliferate in the neointima. The accumulation of SMCs and deposition of extracellular matrix lead to a hemodynamically compromising luminal reduction, which is developed in a fraction of the time needed for the primary atherosclerotic lesion. In addition, the neointima is primarily made up of SMCs while the primary lesion is multicellular and without a dominant cell type. To prevent recurrent stenosis, this rapid accumulation of SMCs in the neointima must be inhibited; however, only minimal information is currently available on the mechanisms of accelerated SMC accumulation in the neointima. Preliminary data for this proposal indicate that migration of SMCs is critical in the development of the neointimal lesion, and the work proposed here focuses on the mechanisms of SMC migration and possible techniques to inhibit it. SMC migration is activated by chemotactic and chemokinetic signals generated following arterial injury and is mediated by interaction of SMC, integrins expressed on the cell surface and the extracellular matrix. This proposal will test the hypotheses that SMC migration can be inhibited by disrupting the actions of those mediators (e.g. growth factors, integrins and extracellular matrix) and, in turn, the neointimal lesion formation can be prevented. The mechanisms of action on the SMC by the activating signals, platelet-derived growth factor and transforming growth factor-beta, will be delineated. The role of integrin receptors (e.g. alpha-v-beta-3) and the extracellular matrix in SMC migration will be examined. To assess cell migration, in vitro and in vivo cell migration assays will be performed. To determine the effect of inhibition of SMC migration on the neointimal lesion formation, animal studies will be performed with the appropriate agonists and antagonists. The results from these studies may provide new and valuable information on the mechanism of SMC migration and inhibition of the neointimal lesion as well as insight into the development of atherosclerosis.

作为再狭窄的主要原因，新的增生是常见的 小口径嫁接，内膜切除术和气囊血管成形术。 在手术壁上损伤动脉壁后，激活的平滑肌 细胞（SMC）迁移，然后在新内膜中增殖。 这 SMC的积累和细胞外基质的沉积导致A 血流动力学损害的腔腔减少，这是在 原发性动脉粥样硬化病变所需的一小部分时间。 此外，新内膜主要由SMC组成 原发性病变是多细胞的，没有主要细胞类型。 到 防止复发性狭窄，SMC在 必须抑制新内膜；但是，只有最小信息是 目前可用于加速SMC积累机理 在新的。该提案的初步数据表明 SMC的迁移对于新内膜的发展至关重要 病变，此处提出的工作重点介绍了SMC的机制 迁移和抑制它的可能技术。 SMC迁移被趋化和趋化植物信号激活 动脉损伤后产生，并通过相互作用介导 SMC，整联蛋白在细胞表面和细胞外表达 矩阵。该建议将检验SMC迁移可以的假设 通过破坏这些调解人的行为来抑制（例如增长 因素，整联蛋白和细胞外基质），然后 可以防止新的病变形成。作用机理 通过激活信号，血小板衍生的生长因子在SMC上 并将变化生长因子β将被描述。的作用 整联蛋白受体（例如α-V-Beta-3）和细胞外基质 在SMC迁移中将进行检查。为了评估细胞迁移，体外 并将进行体内细胞迁移测定。确定 抑制SMC迁移对新内膜病变的影响 形成，将使用适当的动物研究进行 激动剂和对手。这些研究的结果可能会提供 有关SMC迁移机制和 抑制新内膜病变以及对 动脉粥样硬化的发展。