ARTERY WALL CONTRACTION, WOUND HEALING, AND RESTENOSIS

动脉壁收缩、伤口愈合和再狭窄

• 批准号: 6724944
• 负责人: Randolph L. Geary
• 金额: $ 32.4万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-05-01 至 2007-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6724944
• 关键词: Macaca fascicularis; artery stenosis; atherosclerosis; carbohydrate receptor; carotid artery; cell cycle; cell migration; collagen; extracellular matrix; fibroblasts; gene targeting; genetically modified animals; hyaluronate; immunocytochemistry; in situ hybridization; intermolecular interaction; intraluminal angioplasty; laboratory mouse; microarray technology; muscle contraction; northern blottings; protein structure function; restenosis; tissue /cell culture; vascular smooth muscle; wound healing

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.

描述(由申请人提供)：超过300万个程序(例如 血管成形术)，以打开堵塞的动脉。不幸的是， 每三个人中就有一个会在短期内因 修复，称为再狭窄。再狭窄传统上被归因于 平滑肌细胞及其细胞外基质在血管内皮细胞部位的积聚 受伤。最近，动脉壁在愈合时收缩(向内或 缩窄性重塑)对管腔狭窄的影响更大 血管成形术后较新生壁肿块本身。细胞和分子基础 对重塑的定义并不明确。这就是这项研究的总体目标 计划是定义驱动收缩重塑的机制 血管成形术。HA是一种大的糖胺聚糖，主要存在于基质中，沉积在 血管成形术和重塑的部位。众所周知，羟基磷灰石可以增强胶原蛋白 伤口中成纤维细胞的重组，并加速伤口闭合，促使 损伤动脉中胶原-透明质酸相互作用的研究热点 墙。透明质酸受体对动脉平滑肌细胞的生长和 体外迁移。透明质酸的存在增强了胶原的收缩 并受阻断HA受体的限制。HA的片段已经被开发成 阻断HA受体，抑制大鼠和兔的内膜增生。 胶原蛋白和透明质酸是修复反应的重要成分 动脉粥样硬化的血管成形术和PI的研究表明 管壁收缩的机制是平滑肌细胞的胶原重组 外膜成纤维细胞。这项提案旨在利用HA受体基因敲除 小鼠研究这些受体在血管平滑肌细胞收缩中的作用 胶原凝胶的体外研究及HA受体缺失对颈动脉的影响 活体动脉缩窄性重构。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检验这样的假设： 选择性HA受体拮抗剂输注4周将抑制动脉壁 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在收缩重构过程中诱导的模式 损伤后，以及从体外收缩胶原的平滑肌细胞，到 人类基因阵列。