METALLOPROTEASE DEPENDENT FIBRINOLYSIS AND ANGIOGENESIS

在肿瘤发生、炎症和伤口愈合期间，血管生成主要通过血管生成蛋白的分泌来启动，血管内皮生长因子（VEGF）触发纤维蛋白网的沉积，该纤维蛋白网与I型胶原蛋白一起充当进入血管的基质。 同时，VEGF单独或与其他生长因子组合，启动六步程序，包括：i）内皮细胞-细胞和细胞-基质相互作用的破坏，ii）内皮下基底膜的蛋白水解降解，iii）运动表型的表达，iv）通过基质/间质基质的侵入，v）增殖和vi）形态发生程序的激活，其允许未闭小管、紧密连接以及基底膜的再生。 目前，内皮细胞侵入纤维蛋白和富含I型胶原的沉积物并重塑周围细胞外基质以产生通畅的新血管的机制仍不明确。 虽然最近的研究集中在纤溶酶原激活剂轴在新血管形成中的作用，新的发现已经确定了一个以前未知的作用，内皮细胞衍生的基质金属蛋白酶在血管形成。 根据这些结果，提出了以下三个目标：i）鉴定基质金属蛋白酶和纤溶酶原激活剂在体外和体内新血管形成过程中的相对作用，ii）确定单个基质金属蛋白酶在调节内皮细胞增殖、运动、侵袭和小管形成中的作用，iii）表征基质金属蛋白酶在调节纤连蛋白基质组装中作为治疗干预的新下游靶标的作用。 总之，概述的研究不仅应该建立蛋白酶在病理生理过程中调节新血管生长的基本机制，而且还有助于确定新的靶点以及干预不同疾病状态的治疗方法。

Metalloprotease-Dependent Fibrinolysis and Angiogenesis During tumorigenesis, inflammation and wound healing, angiogenesis is initiated largely via the secretion of the angiogenic protein, vascular endothelial growth factor (VEGF) triggers the deposition of a fibrin meshwork that in concert with type I collagen, acts as a substratum for ingressing blood vessels. Concurrently, VEGF alone or in combination with other growth factors, initiates a six step program that involves; i) a disruption of endothelial cell-cell and cell-matrix interactions, ii) proteolytic degradation of the subendothelial basement membrane, iii) the expression of a motile phenotype, iv) invasion through the stromal/interstitial matrix, v) proliferation and vi) activation of a morphogenic program that allows for the regeneration of patent tubules, tight junctions as well as the basement membrane. Presently, the mechanisms by which endothelial cells invade fibrin and type I collagen-rich deposits and remodel the surrounding extracellular matrix to generate patent neovessels remain undefined. While recent studies have focused on the role of the plasminogen activator axis in neovascularization, new findings have identified a previously unsuspected role for endothelial cell-derived matrix metalloproteinases in blood vessel formation. Based on these results, the following three aims are proposed: i) identify the relative roles of matrix metalloproteinases and plasminogen activators in the neovascularization process in vitro and in vivo, ii) define the role of individual matrix metalloproteinases in regulating endothelial cell proliferation, motility, invasion and tubulogenesis, iii) characterize the role of matrix metalloproteinases in regulating fibronectin matrix assembly as a new downstream target for therapeutic intervention. Together, the outlined studies should not only establish the basic mechanisms by which proteinases regulate neovessel growth during pathophysiologic processes, but also assist in the identification of new targets as well as therapeutics for intervention in diverse disease states.