METALLOPROTEASE DEPENDENT FIBRINOLYSIS AND ANGIOGENESIS

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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.