One of the cellular components of normal wound repair is angiogenesis, the formation of new blood vessels. Wound repair angiogenesis requires activation of fibrinolytic enzymes for cellular migration of microvascular endothelial cells through a fibrin matrix. These fibrinolytic enzymes include the plasminogen activator system, which consists of urokinase plasminogen activator (uPA) and tissue plasminogen activator (tPA), balanced by plasminogen activator inhibitor-1 (PAI-1), which limits plasmin generation and excessive fibrinolysis. Mechanisms that regulate plasminogen activators in vivo and the requirement for the plasminogen activator system in wound healing angiogenesis remain undefined. Vitronectin, a glycoprotein found in plasma and deposited at the site of tissue injury, has no defined role in vivo. Vitronectin can bind free PAI-1 , and this complex can bind to the endothelial cell surface receptor for uPA, uPAR. Competition for uPAR determines the balance between fibrinolysis and inhibition. Whereas these regulatory mechanisms have been demonstrated in vitro, the investigators propose to demonstrate that vitronectin modulates the plasminogen activator system in angiogenesis during response to injury. Transgenic mice deficient for vitronectin or the plasminogen activator system gene products appear phenotypically normal. The investigator's preliminary data indicate that in vivo, vitronectin functions as a regulator of fibrinolysis, especially important for endothelial cell migration. The preliminary data also show for the first time that the vitronectin: PAI-1 complex binds growth factors cited to be important for angiogenesis. These data suggest that interaction between vitronectin, the PA system, and growth factors are an important component of endothelial cell response to injury and angiogenesis. The investigator will use a wound healing model in gene-targeted mice deficient in vitronectin, uPA, tPA, or uPAR to define the individual functions for vitronectin and the PA system for neovascularization after tissue injury.
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