The major objective of this proposal is to define a specific role for collagen degradation and tissue remodeling during angiogenesis. The investigator proposes to examine the functional significance of proteolytic modification of interstitial collagen type-I, a major component of the vascular extracellular matrix that has historically been considered as a structural component regulating tissue morphogenesis and stability. Angiogenesis has been suggested to depend on both cell adhesion and proteolytic mechanisms. However, to date, little is known concerning how cell adhesion receptors and proteolytically degraded extracellular matrix (ECM) components function cooperatively in the regulation of angiogenesis in vivo. The potential cellular and biochemical mechanisms by which proteolytically degraded collagen and resulting fragments can function as a ligand for vascular integrin alphav beta3, potentiating endothelial cell survival and angiogenesis will be examined. The hypothesis is that matrix metalloproteinases (MMPs), the primary class of enzymes capable of specifically degrading interstitial collagen, are up regulated and selectively associated with angiogenic blood vessels in vivo. It will be determined whether the elevated levels of MMPs are expressed in a proteolytically active form that could initiate the formation of proteolyzed interstitial collagen in the immediate microenvironment of angiogenic blood vessels. The ability of proteolytic degradation of collagen to reveal cryptic adhesive sequences that provide a physiologically important ligand for vascular integrin alphav beta3-mediated event necessary for the ligation of endothelial cell survival and angiogenesis will be tested. Since angio-genesis plays a critical role in a variety of normal and pathological processes, understanding the molecular events that regulate this process is of paramount importance, not only to our basic understanding of angiogenesis, but also to the design of novel strategies for the treatment of diseases characterized by neovascularization. Therefore, this study should provide new information to bridge the gap in our understanding of the complex mechanisms that regulate new blood vessels formation in vivo and provide the first evidence for a specific role for proteolyzed collagen in the regulation of endothelial cell survival and angiogenesis.
