SMOOTH MUSCLE CELLS AND GRAFT INTIMAL HYPERPLASIA

我们研究的长期目标是提高假体的通畅性 通过控制内膜增生来控制血管移植物。 内膜增生 其特征在于平滑肌细胞（SMC）积聚和基质 沉积物，并且在假体假体周围最严重 移植物 我们对内皮细胞（EC）种植移植物的研究表明， 血小板衍生生长因子产生的时间依赖性增加 血小板源性生长因子（PDGF），这是与SMC的外观在内部 移植物的包膜。 初步的体外研究表明， 与主动脉SMC相比，SMC发生了显著变化;移植SMC产生 高水平的PDGF，在最低限度的血清中增殖，生长较少 与主动脉SMC相比，对肝素的抑制作用敏感。 我们推测 平滑肌细胞迁移到内囊并在内囊中增殖， 移植物被修饰以产生有丝分裂原， 自分泌方式 此外，我们建议， SMC对天然生长刺激剂和抑制剂的反应发生了改变， 抑制内膜增生最有效的方法是阻断一种常见的 多种有丝分裂原受体和细胞分裂之间的途径。 为了验证这些假设，生产和响应生长调节剂， 将被研究。 PDGF A链、B链、碱性成纤维细胞的生产 生长因子（bFGF）和转化生长因子β（TGF β）， 定向生长调节剂，将比较移植物和主动脉EC， SMC。 确定工作人员和管理层委员会应对 有丝分裂原、受体数量和PDGF、bFGF和 将在移植物和主动脉SMC中研究TGF β。 此外，本发明还提供了一种方法， 移植物和动脉SMC对PDGF的增殖和迁移反应- 将比较AA、AB、-BB、bFGF、TGF β和肝素。 差异是否 在有丝分裂原或抑制剂产生或反应中， 移植物和动脉平滑肌细胞在体外，基因表达水平将 确定，mRNA的差异与基因的变异有关， 转录速率或信息稳定性。 为了确定SMC是否 移植物上的增殖可以通过阻断晚期常见的 c-myb反义核酸抑制细胞分裂的作用 将在体外和体内研究SMC增殖。 由移植物衬里的SMC产生的有丝分裂原可能是导致 SMC持续迁移和增殖以及基质沉积 引起移植物的新生内膜增生。 拟议的研究将导致 更好地了解有丝分裂原产生的变化， SMC衬里人工血管移植物的反应，以及 通过阻断细胞分裂中的共同途径来抑制增殖。 最终，这可能导致干预，以抑制有丝分裂反应 并控制吻合口内膜增生的发展。

The long-term goal of our research is to improve patency of prosthetic vascular grafts by controlling intimal hyperplasia. Intimal hyperplasia is characterized by smooth muscle cell (SMC) accumulation and matrix deposition, and is most severe adjacent to the anastomoses of prosthetic grafts. Our studies of endothelial cell (EC) seeded grafts demonstrate a time-dependent increase in production of platelet-derived growth factor (PDGF), which is associated with the appearance of SMC in the inner capsule of the graft. Preliminary in vitro studies suggest that graft SMC are significantly modified compared to aortic SMC; graft SMC produce high levels of PDGF, proliferative in minimal serum, and growth is less sensitive to inhibition by heparin compared to aortic SMC. We postulate that SMC that migrate to, and proliferate in, the inner capsule of the graft are modified to produce mitogens to which they respond in an autocrine fashion. Furthermore, we propose that the response of graft SMC to natural growth stimulators and inhibitors is altered, and that the most effective method to inhibit intimal hyperplasia is to block a common pathway between the multiple mitogen receptors and cell division. To test these hypotheses, production and response to growth regulators will be studied. Production of PDGF A-chain, B-chain, basic fibroblast growth factor (bFGF), and transforming growth factor beta (TGFBeta) a bi- directional growth regulator, will be compared in graft and aortic EC and SMC. To determine differences in the capacity of SMC to respond to mitogens, receptor number and affinity of binding of PDGF, bFGF, and TGFBeta will be studied in graft and aortic SMC. In addition, proliferative and migratory responses of graft and arterial SMC to PDGF- AA, AB, -BB; bFGF; TGFBeta; and heparin will be compared. If differences in mitogen or inhibitor production or response are identified between graft and artery SMC in vitro, the level of gene expression will be determined, and differences in mRNA related to variation in gene transcription rates or message stability. To determine if SMC proliferation on grafts can be inhibited by blocking a late common pathway of cell division, the efficacy of antisense to c-myb to inhibit SMC proliferation will be studied in vitro and in vivo. Production of mitogens by SMC lining the graft may be responsible for continued SMC migration and proliferation as well as matrix deposition causing neointimal hyperplasia of grafts. The proposed studies will lead to a better understanding of alterations in mitogen production and response by SMC lining prosthetic vascular grafts, and the ability to suppress proliferation by blocking the common pathway in cell division. Ultimately, this may lead to interventions to inhibit mitogenic responses and control the development of anastomotic intimal hyperplasia.