REGULATION OF KININ DELIVERY ON HUVEC

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DESCRIPTION (Applicant's abstract): The hypothesis that forms the basis of this proposal is that the assembly of high molecular weight kininogen on a multiprotein kininogen receptor results in regulated activation of the enzymes of the plasma kallikrein/kinin system. Activation of the proteins of the plasma kallikrein/kinin system (high molecular weight kininogen, prekallikrein, and factor XII) influences vascular biology by modulating vascular tone and the constitutive antithrombotic nature of the intravascular compartment. Understanding the function of the plasma kallikrein/kinin system is still in its infancy. The fact that deficiencies of these proteins gave abnormal surface-mediated coagulation assays incorrectly oriented earlier investigators to the role of these proteins in intrinsic coagulation. The purpose of these investigations is to develop new understandings of this system's contribution to vascular biology. The specific aims of this proposal are as follows: Specific Aim #1: The endothelial cell plasma prekallikrein activator that initiates activation of the plasma kallikrein/kinin system will be identified and characterized. Specific Aim #2: The interactions of high molecular weight kininogen and factor XII with the urokinase plasminogen activator receptor (uPAR) will be characterized. Specific Aim #3: Animal models for thrombosis will be utilized to ascertain the contributions of bradykinin B2 receptors to the constitutive anticoagulant nature of the intravascular compartment. These investigations will determine physiological activities that define the plasma kallikrein/kinin system. These studies are intended to characterize this system's contribution to vascular biology and to develop new strategies to modulate intravascular thrombosis.