Urokinase (uPA) is a multifunctional protein that has been implicated in several pathophysiological processes such as cancer, angiogenesis, and inflammation. In addition to its fibrinolytic activity, we recently observed that uPA and its major fragments regulate the contraction of isolated aortic rings and modulate blood pressure in rats. The contribution of uPA-mediated vascular reactivity to fibrinolysis or these other pathophysiologic events has not been investigated and is the subject of this grant.
In Specific Aim 1, we propose to examine the contribution of the uPA growth factor domain and """"""""connecting peptide"""""""" to vasorelaxation and the role of the kringle in vasoconstriction and their regulation by uPAR and PM- 1. We will explore the role of the low-density lipoprotein related receptor in generating bioactive fragments from uPA and the involvement of b integrins as potential signal transducing-kringle binding proteins. The elements in the uPA-kringle that regulate vasoactivity will be examined.
In Specific Aim 2, we will study the mechanism by which uPA modulates vasoreactivity. We will examine role of endogenous uPA, uPAR and PAl-I in regulating blood pressure in transgenic mice lacking these proteins. uPA-mediated vascular contractility will be examined in mice lack PGI2 receptors and critical enzymes in the prostaglandin pathway, including COX-1 and COX-2 In Specific Aim 3, we will examine the relative contribution of uPA-mediated vasoreactivity and proteolysis in a model of pulmonary microembolism developed in our laboratory that is dependent on the actions of uPA. We hypothesize that the capacity of uPA to regulate vascular tone contributes to its fibrinolytic activity as well as to other uPA-mediated signal transduction events such as cell adhesion and migration. Identification of vasoactive components in uPA and their receptors will provide insight into the pathophysiology of these disorders and identify novel targets for therapeutic intervention.
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