ARTERY WALL CONTRACTION, WOUND HEALING, AND RESTENOSIS

描述（由申请人提供）：超过300万个程序（例如 血管成形术）每年进行开放阻塞的动脉。不幸的是， 三分之一的人将在短期内因经常性堵塞而失败， 修复，称为再狭窄。传统上，缓刑被归因于 平滑肌细胞和它们的细胞外基质积聚在 损伤最近，动脉壁在愈合时的收缩（向内或向内）， 缩窄性重塑）对管腔狭窄的贡献更大 比血管成形术后新的壁质量本身。细胞和分子基础 重塑的定义很模糊这是研究的主要目标 计划是定义机制驱动收缩性重塑后， 血管成形术HA是一种大的糖胺聚糖，主要存在于基质中， 血管成形术和重塑的部位。已知HA可增强胶原蛋白 通过伤口中的成纤维细胞进行重组并加速伤口闭合， 损伤动脉中胶原-HA相互作用的研究热点 墙HA受体对于动脉平滑肌细胞生长是重要的， 体外迁移。胶原蛋白的收缩在HA的存在下增强 并通过阻断HA受体而受到限制。HA片段已被开发用于 阻断HA受体，抑制大鼠和家兔内膜增生。 胶原蛋白和HA是创伤后愈合反应的主要成分。 动脉粥样硬化动脉血管成形术和PI的研究表明， 血管壁收缩的机制是平滑肌细胞的胶原重组 和外膜成纤维细胞。该提案旨在采用HA受体敲除 研究这些受体在平滑肌细胞收缩中的作用。 体外胶原凝胶和HA受体缺失对颈动脉的影响 体内动脉收缩重构。一种独特的血管成形术模型， 动脉粥样硬化的猴子也将被用来测试假设， 选择性HA受体拮抗剂输注4周可抑制动脉壁 狭窄和再狭窄。单独的研究将探索基因表达 应用来自动脉的RNA在收缩性重构期间诱导的模式 损伤后，从平滑肌细胞在体外收缩胶原蛋白， 人类基因阵列

Description (provided by applicant): More than 3 million procedures (eg angioplasty) are performed each year to open blocked arteries. Unfortunately, one in three will fail in the short term from recurrent blockage at the site of repair, termed restenosis. Restenosis has traditionally been attributed to the accumulation of smooth muscle cells and their extracellular matrix at sites of injury. More recently, shrinkage of the artery wall as it heals (inward or constrictive remodeling) has been found to contribute more to lumen narrowing after angioplasty than new wall mass per se. The cellular and molecular basis of remodeling is poorly defined. This the broad objectives of the research program are to define mechanisms driving constrictive remodeling after angioplasty. HA is a large glycoaminoglycan prominent in matrix deposited at sites of angioplasty and remodeling. HA is known to enhance collagen reorganization by fibroblasts in wounds and to speed wound closure, prompting the focus of the research on collagen-HA interactions in the injured artery wall. HA receptors are important for arterial smooth muscle cell growth and migration in vitro. Contraction of collagen is enhanced in the presence of HA and limited by blocking HA receptors. Fragments of HA have been developed to block HA-receptors and inhibit intimal hyperplasia in rats and rabbits. Collagen and HA are prominent components of the healing response after angioplasty in atherosclerotic arteries and the PI's studies suggest that the mechanism of wall shrinkage is collagen reorganization by smooth muscle cells and adventitial fibroblasts. This proposal aims to employ HA-receptor knockout mice to study the role of these receptors in smooth muscle cells contraction of collagen gels in vitro and the impact of HA-receptor deletions on carotid artery constrictive remodeling in vivo. A unique model of angioplasty in atherosclerotic monkeys will also be used to test the hypothesis that a non selective HA receptor antagonist infused for 4 weeks will inhibit artery wall constriction and restenosis. Separate studies will explore the gene expression patterns induced during constrictive remodeling by applying RNA from arteries after injury, and from smooth muscle cells contracting collagen in vitro, to human gene arrays.