Metalloprotease-Dependent Fibrinolysis and Angiogenesis

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DESCRIPTION: During the neovascularization process associated with physiologic as well as pathologic states, a variety of growth factors initiate an angiogenic response which induces endothelial cells to cross their underlying basement membrane and to infiltrate the surrounding interstitial matrix. The collagen-fibrin matrix then acts as a substratum for ingressing blood vessels. Concurrently, angiogenic growth factors such as VEGF, working alone or in combination with other growth factors, regulates the expression of endothelial cell adhesion molecules and proteinases which allow the cells to penetrate collagen/fibrin barriers, and undergo a tubulogenic program. While a range of anti-angiogenic therapeutics have shown promising effects in animal models - and even in humans - with regard to disease states associated with tumorigenesis/metastasis as well as inflammation, little is known with regard either to the identity of the proteinases that regulate the development of neovessels at pathologic sites, or the factors that regulate their expression. Indeed, whereas a number of collagenolytic and fibrinolytic cascades have been posited to play a critical role in angiogenesis, we have recently identified a small family of membrane-anchored metalloproteinases that appear to play a dominant role in driving blood vessel formation. Based on new findings which support a role for MT1-MMP in basement membrane invasion, endothelial cell invasion and proliferation as well as morphogenesis, we propose to i) Define the role of MT1-MMP in endothelial cell-mediated basement membrane degradation and perforation, ii) characterize the role of MT1-MMP in basement membrane turnover during in vivo angiogenesis, iii) define the growth regulatory properties of endothelial cell MT1-MMP, iv) characterize the morphogen-inducing properties of MT1-MMP that regulate neovessel formation and v) compare and contrast the proteolytic machinery mobilized by lymphatic endothelium that drive invasion, proliferation and branching tubulogenesis. Together, the outlined studies should help establish the basic mechanisms by which proteinases regulate neovessel growth during physiologic as well as pathologic states, and may assist in the identification of new targets for intervention.