PAI-1 and Vitronectin in Failure of Coronary Revascularization

Summary

Principal Investigator: William P Fay
Abstract: DESCRIPTION (provided by applicant): Plasminogen activator inhibitor-1 (PAI-1) is the primary inhibitor of tissue- and urinary-type plasminogen activators. Vitronectin (VN) is an adhesive glycoprotein present in extracellular matrix (ECM) and plasma that stabilizes PAI-1 and whose function is regulated by PAI-1. PAI-1 and VN play major roles in regulating vascular smooth muscle cell (VSMC) migration and intimal hyperplasia, which cause restenosis after percutaneous coronary intervention (PCI) and are central processes in the development of atherosclerosis and other human vascular diseases. Available studies suggest that PAI-1 and VN can either promote or inhibit VSMC migration and intimal hyperplasia, depending on experimental conditions. However, previous in vitro studies have been limited by the fact that they largely involved 2-dimensional cell culture systems and purified reagents, which do not adequately model the ECM in which VSMC migrate in vivo or assess the functions of PAI-1 and VN produced by VSMC themselves. We have developed an experimental model to study the migration of VSMC with genetic alterations in PAI-1 and VN expression through 3-dimensional matrices composed of collagen, VN, and other ECM molecules. Our preliminary data suggest that the stoichiometric relationship of PAI-1 and VN plays a critical role in determining PAI-1's pro- and anti-migratory effects, and that PAI-1 regulates VN expression by VSMC. Available in vivo data regarding the roles of PAI-1 and VN in regulating arterial remodeling have been derived nearly exclusively from experiments with knockout mice. While these studies have yielded a wealth of information, they have been controversial. Consequently, a clear consensus regarding the net effect of PAI-1 on arterial remodeling is lacking, which has hindered development of pharmacological strategies to target PAI-1 to treat or prevent human vascular disease. We hypothesize that elucidation of the authentic function of PAI-1 in human vascular diseases will require experiments involving clinically relevant forms of vascular injury in animals whose vascular size, structure, and function more closely resembles those of humans. Consequently, we have developed a porcine model of PCI and a panel of specific, pharmacological PAI-1 inhibitors that disrupt PAI-1 function by several distinct mechanisms. Our preliminary data with this large animal model suggest that a dominant-negative form of PAI-1 inhibits intimal hyperplasia after PCI. In the proposed experiments we will probe the functions of PAI-1 and VN in vascular remodeling by employing 3-dimensional VSMC migration assays, studying vascular remodeling in mice with a spectrum of PAI-1 and VN expression levels, and determining the effects of a panel of recombinant PAI-1 proteins and small molecule PAI-1 inhibitors in a murine vascular injury model and a clinically relevant porcine model of PCI. To achieve our objectives we have assembled a diverse team of investigators with considerable expertise in PAI-1 and VN biochemistry, cellular and molecular biology, and pharmacology, as well as in veterinary biomedical sciences and clinical cardiovascular medicine. We anticipate that the experiments outlined in this proposal will help to elucidate the vascular functions of PAI-1 and VN under physiologically and clinically relevant conditions and will help to define the role of PAI-1 targeting compounds as potential agents to prevent and treat human vascular disease. PUBLIC HEALTH RELEVANCE: Each year millions of American undergo percutaneous coronary intervention ("stent") procedures for treatment of coronary artery disease. However, percutaneous coronary interventions can fail due to recurrent narrowing of the artery at the site of angioplasty or formation of a thrombus within the stented segment. This application will study the roles of plasminogen activator inhibitor-1 and vitronectin in the failure of percutaneous coronary interventions.
Funding Period: 2010-09-01 - 2014-07-31
more information: NIH RePORT

Top Publications

  1. pmc Plasminogen activator inhibitor-1 and vitronectin expression level and stoichiometry regulate vascular smooth muscle cell migration through physiological collagen matrices
    N Garg
    Department of Internal Medicine, University of Missouri School of Medicine and Research Service, Harry S Truman Memorial Veterans Affairs Hospital, Columbia, MO, USA
    J Thromb Haemost 8:1847-54. 2010
  2. pmc Multifaceted role of plasminogen activator inhibitor-1 in regulating early remodeling of vein bypass grafts
    Yan Ji
    Department of Internal Medicine and Medical Pharmacology and Physiology, University of Missouri School of Medicine, Columbia, MO, USA
    Arterioscler Thromb Vasc Biol 31:1781-7. 2011
  3. pmc Thrombosis, physical activity, and acute coronary syndromes
    Arun Kumar
    Department of Internal Medicine, University of Missouri Columbia School of Medicine, 5 Hospital Dr, Columbia, MO 65212, USA
    J Appl Physiol (1985) 111:599-605. 2011

Research Grants

Detail Information

Publications4

  1. pmc Plasminogen activator inhibitor-1 and vitronectin expression level and stoichiometry regulate vascular smooth muscle cell migration through physiological collagen matrices
    N Garg
    Department of Internal Medicine, University of Missouri School of Medicine and Research Service, Harry S Truman Memorial Veterans Affairs Hospital, Columbia, MO, USA
    J Thromb Haemost 8:1847-54. 2010
    ..Vascular smooth muscle cell (VSMC) migration is a critical process in arterial remodeling. Purified plasminogen activator inhibitor-1 (PAI-1) is reported to both promote and inhibit VSMC migration on two-dimensional (D) surfaces...
  2. pmc Multifaceted role of plasminogen activator inhibitor-1 in regulating early remodeling of vein bypass grafts
    Yan Ji
    Department of Internal Medicine and Medical Pharmacology and Physiology, University of Missouri School of Medicine, Columbia, MO, USA
    Arterioscler Thromb Vasc Biol 31:1781-7. 2011
    ..The role of plasminogen activator inhibitor-1 (PAI-1) in vein graft (VG) remodeling is undefined. We examined the effect of PAI-1 on VG intimal hyperplasia and tested the hypothesis that PAI-1 regulates VG thrombin activity...
  3. pmc Thrombosis, physical activity, and acute coronary syndromes
    Arun Kumar
    Department of Internal Medicine, University of Missouri Columbia School of Medicine, 5 Hospital Dr, Columbia, MO 65212, USA
    J Appl Physiol (1985) 111:599-605. 2011
    ..This article reviews the available literature regarding the role of physical activity in determining the incidence of atherosclerotic plaque rupture and the pace and extent of thrombus formation after plaque rupture...

Research Grants31

  1. Carbon monoxide mediated inhibition of intimal hyperplasia
    Edith Tzeng; Fiscal Year: 2013
    ....
  2. ApoE Receptor Biology and Neurodegeneration
    Mary Jo Ladu; Fiscal Year: 2013
    ..This Program will thus provide new and valuable information about how apoE and apoE receptors affect the pathogenesis of Alzheimer's disease. ..
  3. Thrombus Formation and Antithrombotic Intervention
    John H Griffin; Fiscal Year: 2013
    ..New knowledge will contribute to improving prevention, diagnosis and treatment of relevant diseases related to thrombosis. ..
  4. Immune Responses To AAV-Mediated FIX Gene Transfer
    Hildegund C J Ertl; Fiscal Year: 2013
    ..HC ErtI): T Cells to AAV and AAV-Encoded Transgene Products Project 3 (RW Herzog, C Terliorst): Pathways Towards Immune Tolerance to Coagulation Factors Core A (HC ErtI): Administrative Core Core B (S Zliou): Vector Core ..
  5. Diverse Roles of Reactive Oxygen Species and Inflammation in Vascular Disease
    Kathy K Griendling; Fiscal Year: 2013
    ..Ultimately, this research may establish new unifying concepts linking conditions that alter vascular oxidant stress and inflammation to the molecular processes underlying vasculopathies. (End of Abstract) ..
  6. VITAMIN D AND IMMUNOMODULATION IN CORONARY ARTERY DISEASE
    Devendra K Agrawal; Fiscal Year: 2013
    ....
  7. Calcium signaling in the cerebrovascular unit in health and disease
    Mark T Nelson; Fiscal Year: 2013
    ..The long-term objective is to understand blood flow in the brain in health and disease, and by doing so, to reveal exciting novel targets that can be exploited in the treatment of cerebrovascular disease. ..
  8. Leukadherins as novel compounds for treating restenosis
    ROBERTO IRENARDO VAZQUEZ PADRON; Fiscal Year: 2013
    ..This will pave the way for the future discovery of novel therapeutic agents to treat restenosis after PCI as well as other vascular inflammatory diseases. ..
  9. Glycan Modulation of Inflammatory Responses
    Ajit P Varki; Fiscal Year: 2013
    ..abstract_text> ..
  10. CARDIOVASCULAR DYNAMICS AND THEIR CONTROL
    John E Hall; Fiscal Year: 2013
    ..End of Abstract) ..
  11. KLF4-Dependent Regulation of SMC Differentiation and Phenotypic Switching
    Gary K Owens; Fiscal Year: 2013
    ..abstract_text> ..
  12. MESENCHYMAL STEM CELLS IN THE PREVENTION OF THROMBOSIS AND NEOINTIMAL HYPERPLASIA
    Devendra K Agrawal; Fiscal Year: 2013
    ....
  13. Novel Approaches in Treatment of Vascular Injury Following Balloon Angioplasty
    YEVGENIYA EMRE KOSHMAN; Fiscal Year: 2013
    ..I believe that the questions addressed by this project have fundamental importance to future therapies for vascular remodeling in arterial diseases such as atherosclerosis and restenosis. ..
  14. Vascular endoluminal cellular paving using acoustic radiation force
    Catalin Toma; Fiscal Year: 2013
    ..If successful, these translational experiments could represent the basis developing clinically relevant strategies for accelerated re-endothelialization of coronary stents. ..
  15. Improved Therapeutics for Drug Eluting Stents
    Alyssa Panitch; Fiscal Year: 2013
    ..This proposal focuses on new DESs that promote endothelialization while preventing intimal hyperplasia and thrombosis. ..
  16. PTN FUNCTION IN INTIMAL THICKENING
    PREDIMAN KRISHAN SHAH; Fiscal Year: 2013
    ....
  17. TGF-Beta in Intimal Hyperplasia after Vascular Bypass
    K Craig Kent; Fiscal Year: 2013
    ..The long-term goal is to develop specific therapies that prevent or halt the progression of arterial restenosis, thus reducing morbidity and mortality for thousands of individuals each year. ..
  18. Vascular Oxidases in Migration
    Kathy K Griendling; Fiscal Year: 2013
    ..Understanding the mechanisms underlying migration may lead to the development of new therapeutic strategies that can be carefully and specifically targeted to the critically important events in disease initiation. ..
  19. GENE THERAPY WITH SOCS-3 IN INTIMAL HYPERPLASIA AND IN-STENT RESTENOSIS
    Devendra K Agrawal; Fiscal Year: 2013
    ..The proposed studies will provide conceptual support of our hypothesis and position us to translate our investigation into a clinical phase 1 study for the gene delivery in patients with coronary artery disease. ..
  20. Protein Phosphatase Inhibitor-1 and vascular smooth muscle cell function
    Lahouaria Hadri; Fiscal Year: 2013
    ..Defining the mechanisms of I-1 and its physiological consequences, will be of great relevance in the analysis and future proposal of therapies to prevent and perhaps reverse neointima formation after angioplasty. ..
  21. INTEGRATED MECHANISMS OF CARDIAC MALADAPTATION
    R John Solaro; Fiscal Year: 2013
    ..Studies proposed here offer the potential for novel diagnostic procedures early in the progression of the disorders, and targets for novel therapies. (End of Abstract) ..
  22. Vascular Subphenotypes of Lung Disease
    Mark T Gladwin; Fiscal Year: 2013
    ..vascular disease Project 3: Pulmonary vascular-targeted NO therapeutic strategies Core A: Administrative core Core B: Pre-Clinical Models of PAH Core C: Translational Vascular Phenomics, Genomics and Epidemiology Core ..