Genomes and Genes
PAI-1 and Vitronectin in Failure of Coronary Revascularization
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
- Plasminogen activator inhibitor-1 and vitronectin expression level and stoichiometry regulate vascular smooth muscle cell migration through physiological collagen matricesN 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...
- Multifaceted role of plasminogen activator inhibitor-1 in regulating early remodeling of vein bypass graftsYan 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...
- Thrombosis, physical activity, and acute coronary syndromesArun 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...
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