Fibrotic effects and regulation of MMP proteins in thrombus resolution

Summary

Principal Investigator: Rajabrata Sarkar
Abstract: Deep venous thrombosis (DVT) affects more than 2 million Americans per year. Post-phlebitic syndrome can affect 25-75% of patients following DVT and includes leg swelling, pain, skin changes and ulceration of the skin. This develops only in a subset of DVT patients, suggesting that thrombus resolution is critical in determining whether chronic venous obstruction and fibrosis will develop and lead to post-phlebitic syndrome. Matrix metalloproteinase (MMP) genes, critical to cell migration and tissue remodeling, are expressed and activated during thrombus resolution suggesting a critical role in this process. Their role in the pathogenesis of post-phlebitic syndrome will be defined with three Specific Aims: 1) To define the regions of the MMP-2 gene and cognate transcription factors critical to thrombus-induced MMP-2 expression, 2) To determine the role of MMP-2, MMP-9 and MMP-14 (MT-MMP-f) in DVT resolution and thrombus-induced vein wall fibrosis, 3) To determine if overexpression of MMP proteins (MMP-2, MMP-9 and MMP-14) accelerates DVT resolution and alters thrombus-induced vein wall fibrosis. A unique series of transgenic MMP-2 reporter mice will be used to determine which regions of the MMP-2 gene are essential for thrombus-induced MMP-2 transcription and chromatin immunoprecipitation will be used to identity the cognate transcription factors. Mice with targeted deletion of various MMP genes will be used to determine the role of these enzymes in thrombus recanalization, vein wall fibrosis and loss of vein wall compliance and elasticity using novel assays of mouse vein biomechanics.Tissue-specific transgenic overexpression of MMP-2, -14 and -9 as well as adenoviral vectors encoding these isoforms will be utilized to overexpress these proteins during thrombus resolution to determine resolution of DVT is accelerated and the effects on fibrosis and vein wall biomechanics.These studies will define the role of MMP proteins in the beneficial and detrimental aspects of thrombus resolution, and characterize potential molecular therapy to prevent post- phlebitic syndrome. RELEVANCE: This proposalwill determine how matrix metalloproteinase proteins cause scarring and thickening of veins after blood clots, which can cause later leg pain, swelling and ulcers. These studies will increase knowledge of how veins are damaged by clots and test new treatments to prevent this damage.
Funding Period: ----------------2006 - ---------------2011-
more information: NIH RePORT

Top Publications

  1. ncbi Therapeutic angiogenesis
    Shant M Vartanian
    Division of Vascular Surgery, University of California, San Francisco, California 94143 0104, USA
    Vasc Endovascular Surg 41:173-85. 2007
  2. pmc Activated protein C accelerates venous thrombus resolution through heme oxygenase-1 induction
    J Gabre
    Center for Vascular and Inflammatory Diseases, Department of Surgery, University of Maryland School of Medicine, Baltimore, MD, USA
    J Thromb Haemost 12:93-102. 2014
  3. pmc A biomechanical analysis of venous tissue in its normal and post-phlebitic conditions
    Kirk C McGilvray
    Orthopaedic Bioengineering Research Laboratory, Department of Mechanical Engineering and School of Biomedical Engineering, 1374 Campus Delivery, Colorado State University, Fort Collins, CO 80523 1374, USA
    J Biomech 43:2941-7. 2010

Detail Information

Publications3

  1. ncbi Therapeutic angiogenesis
    Shant M Vartanian
    Division of Vascular Surgery, University of California, San Francisco, California 94143 0104, USA
    Vasc Endovascular Surg 41:173-85. 2007
    ....
  2. pmc Activated protein C accelerates venous thrombus resolution through heme oxygenase-1 induction
    J Gabre
    Center for Vascular and Inflammatory Diseases, Department of Surgery, University of Maryland School of Medicine, Baltimore, MD, USA
    J Thromb Haemost 12:93-102. 2014
    ..Thrombus resolution is a complex process that involves thrombosis, leukocyte-mediated thrombolysis, and the final resolution of inflammation. Activated protein C (APC) is an anticoagulant that also possesses immunoregulatory activities...
  3. pmc A biomechanical analysis of venous tissue in its normal and post-phlebitic conditions
    Kirk C McGilvray
    Orthopaedic Bioengineering Research Laboratory, Department of Mechanical Engineering and School of Biomedical Engineering, 1374 Campus Delivery, Colorado State University, Fort Collins, CO 80523 1374, USA
    J Biomech 43:2941-7. 2010
    ..The data indicate ligation of the vena cava leads to structural alterations in the ground substance and collagen fiber network...