WOUND HEALING ANGIOGENESIS

伤口愈合血管生成

• 批准号: 6180535
• 负责人: FRANK ISIK
• 金额: $ 13.65万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-06-01 至 2003-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6180535
• 关键词: angiogenesis; burns; cell migration; disease /disorder model; enzyme activity; fibrinogen receptors; fibrinolysis; fibroblast growth factor; gene targeting; genetically modified animals; human tissue; immunocytochemistry; immunoprecipitation; in situ hybridization; intermolecular interaction; laboratory mouse; plasminogen activator; plasminogen activator inhibitors; tissue /cell culture; urokinase; vascular endothelium; vitronectin; western blottings; wound healing

One of the cellular components of normal wound repair is angiogenesis, the formation of new blood vessels. Wound repair angiogenesis requires activation of fibrinolytic enzymes for cellular migration of microvascular endothelial cells through a fibrin matrix. These fibrinolytic enzymes include the plasminogen activator system, which consists of urokinase plasminogen activator (uPA) and tissue plasminogen activator (tPA), balanced by plasminogen activator inhibitor-1 (PAI-1), which limits plasmin generation and excessive fibrinolysis. Mechanisms that regulate plasminogen activators in vivo and the requirement for the plasminogen activator system in wound healing angiogenesis remain undefined. Vitronectin, a glycoprotein found in plasma and deposited at the site of tissue injury, has no defined role in vivo. Vitronectin can bind free PAI-1 , and this complex can bind to the endothelial cell surface receptor for uPA, uPAR. Competition for uPAR determines the balance between fibrinolysis and inhibition. Whereas these regulatory mechanisms have been demonstrated in vitro, the investigators propose to demonstrate that vitronectin modulates the plasminogen activator system in angiogenesis during response to injury. Transgenic mice deficient for vitronectin or the plasminogen activator system gene products appear phenotypically normal. The investigator's preliminary data indicate that in vivo, vitronectin functions as a regulator of fibrinolysis, especially important for endothelial cell migration. The preliminary data also show for the first time that the vitronectin: PAI-1 complex binds growth factors cited to be important for angiogenesis. These data suggest that interaction between vitronectin, the PA system, and growth factors are an important component of endothelial cell response to injury and angiogenesis. The investigator will use a wound healing model in gene-targeted mice deficient in vitronectin, uPA, tPA, or uPAR to define the individual functions for vitronectin and the PA system for neovascularization after tissue injury.

正常伤口修复的细胞成分之一是血管生成， 新血管的形成。 伤口修复血管生成需要 激活纤溶酶以促进细胞迁移 微血管内皮细胞穿过纤维蛋白基质。 这些 纤维蛋白溶解酶包括纤溶酶原激活剂系统， 由尿激酶纤溶酶原激活剂（uPA）和组织纤溶酶原组成 激活剂 (tPA)，由纤溶酶原激活剂抑制剂-1 (PAI-1) 平衡， 这限制了纤溶酶的产生和过度的纤维蛋白溶解。机制 调节体内纤溶酶原激活剂以及对 伤口愈合血管生成中的纤溶酶原激活剂系统仍然存在 不明确的。 玻连蛋白，一种在血浆中发现并沉积在现场的糖蛋白 组织损伤，在体内没有明确的作用。 玻连蛋白可以结合 游离的 PAI-1 ，该复合物可以与内皮细胞表面结合 uPA、uPAR 受体。 uPAR的竞争决定平衡 介于纤溶和抑制之间。鉴于这些监管机制 已在体外得到证实，研究人员建议 证明玻连蛋白调节纤溶酶原激活剂系统 损伤反应期间的血管生成。 缺乏玻连蛋白或纤溶酶原激活剂的转基因小鼠 系统基因产物表现出正常的表型。 调查员的 初步数据表明，在体内，玻连蛋白的作用是 纤维蛋白溶解调节剂，对内皮细胞尤其重要 迁移。 初步数据还首次显示 玻连蛋白：PAI-1 复合物结合生长因子被认为很重要 用于血管生成。这些数据表明，之间的相互作用 玻连蛋白、PA系统和生长因子是重要的 内皮细胞对损伤和血管生成反应的组成部分。 这 研究人员将在基因靶向小鼠中使用伤口愈合模型 缺乏玻连蛋白、uPA、tPA 或 uPAR 来定义个体 玻连蛋白和 PA 系统在新生血管形成中的功能 组织损伤。