ARTERY WALL CONTRACTION, WOUND HEALING, AND RESTENOSIS

描述（由申请人提供）：超过300万个程序（例如 每年都会进行血管成形术，以疏通阻塞的动脉。不幸的是， 三分之一的人会因现场反复堵塞而在短期内失败 修复，称为再狭窄。传统上，再狭窄归因于 平滑肌细胞及其细胞外基质在以下部位的积累 受伤。最近，动脉壁在愈合时收缩（向内或 收缩性重塑）被发现对管腔变窄有更大的贡献 血管成形术后比新壁质量本身更重要。细胞和分子基础 改造的定义不明确。这是研究的广泛目标 计划的目的是定义之后驱动紧缩性重塑的机制 血管成形术。 HA 是一种大的糖胺聚糖，主要沉积在基质中 血管成形术和重塑的部位。 HA 可以增强胶原蛋白 伤口中的成纤维细胞重组并加速伤口闭合，促使 研究重点是损伤动脉中胶原蛋白-HA 相互作用 墙。 HA 受体对于动脉平滑肌细胞的生长很重要 体外迁移。 HA 存在时胶原蛋白的收缩增强 并通过阻断 HA 受体来限制。 HA 片段已被开发为 阻断大鼠和兔子的 HA 受体并抑制内膜增生。 胶原蛋白和透明质酸是术后愈合反应的重要组成部分 动脉粥样硬化动脉血管成形术和 PI 的研究表明 壁收缩的机制是平滑肌细胞的胶原蛋白重组 和外膜成纤维细胞。该提案旨在采用 HA 受体敲除 小鼠研究这些受体在平滑肌细胞收缩中的作用 体外胶原凝胶以及 HA 受体缺失对颈动脉的影响 体内动脉收缩重塑。独特的血管成形术模型 动脉粥样硬化猴子也将被用来检验以下假设： 选择性HA受体拮抗剂输注4周将抑制动脉壁 收缩和再狭窄。单独的研究将探索基因表达 应用动脉 RNA 进行收缩性重塑过程中诱导的模式 受伤后，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.