Regulation of vasoreactivity by urokinase

Summary

Principal Investigator: Abd Al Roof Higazi
Abstract: DESCRIPTION (Applicant's abstract): 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.
Funding Period: 2001-03-05 - 2006-01-31
more information: NIH RePORT

Top Publications

  1. ncbi Fibulin-5 binds urokinase-type plasminogen activator and mediates urokinase-stimulated β1-integrin-dependent cell migration
    Alexander Kapustin
    Faculty of Fundamental Medicine, MV Lomonosov Moscow State University, Moscow, Russia
    Biochem J 443:491-503. 2012
  2. pmc Immunomodulatory effects of plasminogen activators on hepatic fibrogenesis
    A A Higazi
    Department of Clinical Biochemistry, Hadassah University Hospital, Jerusalem, Israel
    Clin Exp Immunol 152:163-73. 2008
  3. ncbi Involvement of the urokinase kringle domain in lipopolysaccharide-induced acute lung injury
    Xue Qing Wang
    Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado, and Health Services Center, Denver, CO 80262, USA
    J Immunol 177:5550-7. 2006
  4. ncbi alpha-Defensin: link between inflammation and atherosclerosis
    Hisham Nassar
    Department of Cardiology, Hadassah Medical Center, Jerusalem, IL 91120, Israel
    Atherosclerosis 194:452-7. 2007
  5. ncbi Neutralizing the neurotoxic effects of exogenous and endogenous tPA
    William M Armstead
    Department of Anesthesiology, University of Pennsylvania, 3620 Hamilton Walk, JM3, Philadelphia, Pennsylvania 19104, USA
    Nat Neurosci 9:1150-5. 2006
  6. ncbi Plasminogen activator inhibitor-1 potentiates LPS-induced neutrophil activation through a JNK-mediated pathway
    Sang Hyun Kwak
    Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Health Sciences Center, Colorado, USA
    Thromb Haemost 95:829-35. 2006
  7. ncbi LRP and alphavbeta3 mediate tPA activation of smooth muscle cells
    Sa ed Akkawi
    Department of Clinical Biochemistry, and Interdepartmental Unit, Hadassah University Hospital and Hebrew University Hadassah Medical School, Jerusalem, Israel
    Am J Physiol Heart Circ Physiol 291:H1351-9. 2006
  8. ncbi Plasminogen activators contribute to impairment of hypercapnic and hypotensive cerebrovasodilation after cerebral hypoxia/ischemia in the newborn pig
    William M Armstead
    Department of Anesthesia, University of Pennsylvania, Philadelphia, PA 19104, USA
    Stroke 36:2265-9. 2005
  9. ncbi The kringle domain of urokinase-type plasminogen activator potentiates LPS-induced neutrophil activation through interaction with {alpha}V{beta}3 integrins
    Sang Hyun Kwak
    Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Health Sciences Center, Denver, CO 80262, USA
    J Leukoc Biol 78:937-45. 2005
  10. ncbi Regulation of the single-chain urokinase-urokinase receptor complex activity by plasminogen and fibrin: novel mechanism of fibrin specificity
    Abd Al Roof Higazi
    Department of Pathology and Laboratory Medicine, 513A Stellar Chance, 422 Curie Blvd, University of Pennsylvania, Philadelphia, PA, 19104, USA
    Blood 105:1021-8. 2005

Scientific Experts

  • Abd Al Roof Higazi
  • William Armstead
  • Khalil Bdeir
  • Sang Hyun Kwak
  • Douglas B Cines
  • Sa ed Akkawi
  • Xue Qing Wang
  • Edward Abraham
  • Alexander Kapustin
  • Hisham Nassar
  • Douglas Cines
  • Sanchayita Mitra
  • Steven Idell
  • Tatiana Lebedeva
  • Vsevolod Tkachuk
  • Grigory Ryzhakov
  • Alex Bobik
  • Mikhail Minashkin
  • Alexander Vorotnikov
  • Robert Beabealashvilli
  • Yaroslav Gursky
  • Serge Yarovoi
  • Natalia Aniol
  • Victoria Stepanova
  • Hiromi Yanagisawa
  • Yelena Parfyonova
  • Alexei Poliakov
  • Robin Wait
  • Samuel N Heyman
  • Ehud Lavi
  • P N Raghunath
  • John Tomaszewski
  • Wen Feng Fang
  • Sergei Yarovoi
  • Qianbin He
  • Victoria A Ploplis
  • Zhi Xu
  • Taher Nassar
  • Mark Tarshis
  • Wenfeng Fang
  • Jael Yeol Kim
  • Derek Strassheim
  • Jong Sung Park

Detail Information

Publications10

  1. ncbi Fibulin-5 binds urokinase-type plasminogen activator and mediates urokinase-stimulated β1-integrin-dependent cell migration
    Alexander Kapustin
    Faculty of Fundamental Medicine, MV Lomonosov Moscow State University, Moscow, Russia
    Biochem J 443:491-503. 2012
    ..We suggest that uPA promotes cell migration by binding to fibulin-5, initiating its cleavage by plasmin, which leads to its dissociation from β1-integrin and thereby unblocks the capacity of integrin to facilitate cell motility...
  2. pmc Immunomodulatory effects of plasminogen activators on hepatic fibrogenesis
    A A Higazi
    Department of Clinical Biochemistry, Hadassah University Hospital, Jerusalem, Israel
    Clin Exp Immunol 152:163-73. 2008
    ..Based on these data we postulate that plasminogen activators affect fibrosis in part by liver-specific activation of CD8 subsets that govern the fibrogenic activity of hepatic stellate cells...
  3. ncbi Involvement of the urokinase kringle domain in lipopolysaccharide-induced acute lung injury
    Xue Qing Wang
    Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado, and Health Services Center, Denver, CO 80262, USA
    J Immunol 177:5550-7. 2006
    ..Blockade of the uPA KD may prevent the development or ameliorate the severity of acute lung injury induced through TLR4-dependent mechanisms, such as would occur in the setting of Gram-negative pulmonary or systemic infection...
  4. ncbi alpha-Defensin: link between inflammation and atherosclerosis
    Hisham Nassar
    Department of Cardiology, Hadassah Medical Center, Jerusalem, IL 91120, Israel
    Atherosclerosis 194:452-7. 2007
    ..We asked, therefore, if alpha-defensins are risk factors for the presence and severity of atherosclerosis...
  5. ncbi Neutralizing the neurotoxic effects of exogenous and endogenous tPA
    William M Armstead
    Department of Anesthesiology, University of Pennsylvania, 3620 Hamilton Walk, JM3, Philadelphia, Pennsylvania 19104, USA
    Nat Neurosci 9:1150-5. 2006
    ..These experiments suggest mechanisms to reduce the neurotoxic effects of tPA without compromising its fibrinolytic activity, through the use of selective antagonists and new tPA formulations...
  6. ncbi Plasminogen activator inhibitor-1 potentiates LPS-induced neutrophil activation through a JNK-mediated pathway
    Sang Hyun Kwak
    Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Health Sciences Center, Colorado, USA
    Thromb Haemost 95:829-35. 2006
    ..These results demonstrate that PAI-1 and uPA KD enhance LPS-induced neutrophil responses through their effects on JNK mediated pathways...
  7. ncbi LRP and alphavbeta3 mediate tPA activation of smooth muscle cells
    Sa ed Akkawi
    Department of Clinical Biochemistry, and Interdepartmental Unit, Hadassah University Hospital and Hebrew University Hadassah Medical School, Jerusalem, Israel
    Am J Physiol Heart Circ Physiol 291:H1351-9. 2006
    ..Delineating the mechanism underlying these interactions and the nature of the signals transduced may provide new tools to regulate vascular tone and other consequences of tPA-mediated signaling...
  8. ncbi Plasminogen activators contribute to impairment of hypercapnic and hypotensive cerebrovasodilation after cerebral hypoxia/ischemia in the newborn pig
    William M Armstead
    Department of Anesthesia, University of Pennsylvania, Philadelphia, PA 19104, USA
    Stroke 36:2265-9. 2005
    ..We investigated the role of exogenous and endogenous plasminogen activators (PA) in piglet hypercapnic and hypotensive dilator impairment after H/I...
  9. ncbi The kringle domain of urokinase-type plasminogen activator potentiates LPS-induced neutrophil activation through interaction with {alpha}V{beta}3 integrins
    Sang Hyun Kwak
    Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Health Sciences Center, Denver, CO 80262, USA
    J Leukoc Biol 78:937-45. 2005
    ..These results demonstrate that the KD of uPA, through interaction with alpha(V)beta(3) integrins, potentiates neutrophil activation...
  10. ncbi Regulation of the single-chain urokinase-urokinase receptor complex activity by plasminogen and fibrin: novel mechanism of fibrin specificity
    Abd Al Roof Higazi
    Department of Pathology and Laboratory Medicine, 513A Stellar Chance, 422 Curie Blvd, University of Pennsylvania, Philadelphia, PA, 19104, USA
    Blood 105:1021-8. 2005
    ..These studies provide insight into the regulation of uPA-mediated plasminogen activation and identify a novel mechanism for its fibrin specificity...