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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL067381-03
Application #
6629159
Study Section
Pathology A Study Section (PTHA)
Program Officer
Goldman, Stephen
Project Start
2001-03-05
Project End
2006-01-31
Budget Start
2003-02-01
Budget End
2004-01-31
Support Year
3
Fiscal Year
2003
Total Cost
$277,375
Indirect Cost
Name
University of Pennsylvania
Department
Pathology
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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Kwak, Sang-Hyun; Wang, Xue-Qing; He, Qianbin et al. (2006) Plasminogen activator inhibitor-1 potentiates LPS-induced neutrophil activation through a JNK-mediated pathway. Thromb Haemost 95:829-35
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Armstead, William M; Cines, Douglas B; Higazi, Abd Al-Roof (2005) Plasminogen activators contribute to impairment of hypercapnic and hypotensive cerebrovasodilation after cerebral hypoxia/ischemia in the newborn pig. Stroke 36:2265-9
Kwak, Sang-Hyun; Mitra, Sanchayita; Bdeir, Khalil et al. (2005) The kringle domain of urokinase-type plasminogen activator potentiates LPS-induced neutrophil activation through interaction with {alpha}V{beta}3 integrins. J Leukoc Biol 78:937-45

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