METALLOPROTEASE DEPENDENT FIBRINOLYSIS AND ANGIOGENESIS

在肿瘤发生、炎症和伤口愈合过程中，血管生成主要是通过血管生成蛋白的分泌而启动的，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型胶原蛋白协同作用，作为进入血管的基质。同时，VEGF单独或与其他生长因子联合，启动一个六步程序，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/间质基质的侵袭，v)增殖和vi)允许未闭小管、紧密连接和基底膜再生的形态发生程序的激活。目前，内皮细胞入侵纤维蛋白和I型胶原丰富沉积物并重塑周围细胞外基质以产生未闭新血管的机制尚不清楚。虽然最近的研究主要集中在纤溶酶原激活剂轴在新生血管中的作用，但新的发现已经确定了内皮细胞来源的基质金属蛋白酶在血管形成中的先前未被怀疑的作用。基于这些结果，提出了以下三个目标：1)确定基质金属蛋白酶和纤溶酶原激活剂在体外和体内新生血管形成过程中的相对作用；2)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；3)表征基质金属蛋白酶在调节纤维连接蛋白基质组装中的作用，作为治疗干预的新下游靶点。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，而且还应该有助于确定新的靶点和治疗方法，以干预不同的疾病状态。

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.