Vein wall remodeling after DVT is matrix metalloproteinase dependent

Summary

Principal Investigator: P K Henke
Abstract: This application's broad, long term objectives are to better define the mechanisms of post deep vein thrombosis (DVT) vein wall remodeling with an eye towards modifying the damage that occurs, and allow translation to human therapy. Post phelbitic syndrome occurs after DVT in a significant number of patients and results in leg pain, swelling, and occasionally ulceration. The costs to society are great in terms of lost productivity, and need for repeated health care visits. While efficacious therapy exists to prevent DVT propagation, none exist that directly modify vein wall damage. The basic mechanisms of vein wall remodeling after DVT include inflammatory cell influx, profibrotic growth factor production, collagen and elastin turnover, and matrixmetalloproteinases (MMP) activation. Specifically, preliminary data strongly suggests that the vein wall responds differently depending on the nature and duration of thrombus contact and is associated with increased MMP-2 and -9 activity. Whether these proteinases are responsible for the early damage and later fibrosis is not known, nor is it possible to predict which patients may develop post- phelbitic syndrome. Currenly available ultrasonographic and peripheral leukocyte genetic expression of MMPs in the setting of acute and chronic DVT is an unstudied area. THE OVERALL HYPOTHESIS IS THAT STASIS THROMBOSIS CAUSES VEIN WALL DAMAGE BY MMP ACTIVATION, LEADING TO LATE FIBROTIC INJURY. The current study will evaluate this hypothesis utilizing in vivo rodent models of DVT and a series of human patients with DVT by the following Specific Aims: I. To investigate in rat model of DVT: A) The mechanism by which thrombotic conditions regulate vein wall MMP-2, -9 expression;and B) To determine if exogenous MMP inhibitors can attenuate early vein wall injury;II. To demonstrate that down-regulation of MMP-2 and -9 activity inhibits late vein wall fibrotic injury after stasis DVT in a mouse model;III. To define ongoing vein wall injury in humans following DVT by duplex ultrasonography, and peripheral leukocyte gene and serum protein MMP-2 and -9 expression. This proposal will provide important mechanistic insight into the pathophysiology of post-phelbitic syndrome with real potential translation to decreasing the morbidity from this under-acknowledged disease.
Funding Period: 2006-04-01 - 2010-03-31
more information: NIH RePORT

Top Publications

  1. pmc Matrix metalloproteinase-9 deletion is associated with decreased mid-term vein wall fibrosis in experimental stasis DVT
    Kristopher B Deatrick
    Conrad Jobst Vascular Research Laboratory, Section of Vascular Surgery, Department of Surgery, University of Michigan Medical School, Boston MA, United States
    Thromb Res 132:360-6. 2013
  2. pmc The effect of matrix metalloproteinase 2 and matrix metalloproteinase 2/9 deletion in experimental post-thrombotic vein wall remodeling
    Kristopher B Deatrick
    Conrad Jobst Vascular Research Laboratory, Section of Vascular Surgery, Department of Surgery, University of Michigan Medical School, Ann Arbor, Mich
    J Vasc Surg 58:1375-1384.e2. 2013
  3. pmc The role of urokinase plasminogen activator and plasmin activator inhibitor-1 on vein wall remodeling in experimental deep vein thrombosis
    Joe F Baldwin
    Jobst Vascular Surgery Laboratory, Section of Vascular Surgery, University of Michigan Medical School, Ann Arbor, MI, USA
    J Vasc Surg 56:1089-97. 2012
  4. ncbi Urokinase plasminogen activator independent early experimental thrombus resolution: MMP2 as an alternative mechanism
    Vikram Sood
    Jobst Vascular Surgery Laboratory, Section of Vascular Surgery, University of Michigan Medical School, Ann Arbor, Michigan, USA
    Thromb Haemost 104:1174-83. 2010
  5. pmc Critical review of mouse models of venous thrombosis
    Jose A Diaz
    Department of Surgery, Conrad Jobst Vascular Research Laboratories, University of Michigan, A570 MSRB II, Dock 6, 1150 W Medical Center Drive, Ann Arbor, MI 48109 0654, USA
    Arterioscler Thromb Vasc Biol 32:556-62. 2012
  6. pmc Toll-like receptor 9 signaling is critical for early experimental deep vein thrombosis resolution
    Peter K Henke
    CVC 5463, Ann Arbor, MI 48109, USA
    Arterioscler Thromb Vasc Biol 31:43-9. 2011
  7. pmc Postthrombotic vein wall remodeling: preliminary observations
    Kristopher B Deatrick
    Section of Vascular Surgery, Department of Surgery, University of Michigan Health System, Ann Arbor, MI, USA
    J Vasc Surg 53:139-46. 2011
  8. ncbi The vessel wall: A forgotten player in post thrombotic syndrome
    Scott Deroo
    Section of Vascular Surgery, Department of Surgery, University of Michigan, Ann Arbor, Michigan, USA
    Thromb Haemost 104:681-92. 2010
  9. pmc Vein wall remodeling after deep vein thrombosis: differential effects of low molecular weight heparin and doxycycline
    Vikram Sood
    Jobst Vascular Surgery Laboratory, Section of Vascular Surgery, University of Michigan Medical School, Ann Arbor, MI, USA
    Ann Vasc Surg 24:233-41. 2010
  10. ncbi Role of selectins and fibrinolysis in VTE
    Thomas W Wakefield
    Department of Surgery, Ann Arbor, MI, USA
    Thromb Res 123:S35-40. 2009

Scientific Experts

  • P K Henke
  • THOMAS WILLIAM contact WAKEFIELD
  • J A Diaz
  • Vikram Sood
  • Kristopher B Deatrick
  • Gilbert R Upchurch
  • Catherine E Luke
  • Megan A Elfline
  • Nicholas A Dewyer
  • Joe F Baldwin
  • Joseph Baldwin
  • Dan D Myers
  • Megan Elfline
  • Scott Deroo
  • K Barry Deatrick
  • Cathy Luke
  • Daria K Moaveni
  • Erin M Lynch
  • Farouc A Jaffer
  • Farouc Jaffer
  • Andrea Obi
  • Cathy E Luke
  • Susan Blackburn
  • Nichole Baker
  • Catherine Stabler
  • Erin M Miller
  • Mayo Mitsuya
  • Erin Miller
  • Steven Kunkel

Detail Information

Publications14

  1. pmc Matrix metalloproteinase-9 deletion is associated with decreased mid-term vein wall fibrosis in experimental stasis DVT
    Kristopher B Deatrick
    Conrad Jobst Vascular Research Laboratory, Section of Vascular Surgery, Department of Surgery, University of Michigan Medical School, Boston MA, United States
    Thromb Res 132:360-6. 2013
    ..Vein wall fibrotic injury following deep venous thrombosis (VT) is associated with elevated matrix metalloproteinases (MMPs). Whether and by what mechanism MMP9 directly contributes to vein wall remodeling after VT is unknown...
  2. pmc The effect of matrix metalloproteinase 2 and matrix metalloproteinase 2/9 deletion in experimental post-thrombotic vein wall remodeling
    Kristopher B Deatrick
    Conrad Jobst Vascular Research Laboratory, Section of Vascular Surgery, Department of Surgery, University of Michigan Medical School, Ann Arbor, Mich
    J Vasc Surg 58:1375-1384.e2. 2013
    ..Vein wall fibrotic injury following deep venous thrombosis (VT) is associated with elevated matrix metalloproteinases (MMPs). Whether and by what mechanism MMP2 contributes to vein wall remodeling after VT is unknown...
  3. pmc The role of urokinase plasminogen activator and plasmin activator inhibitor-1 on vein wall remodeling in experimental deep vein thrombosis
    Joe F Baldwin
    Jobst Vascular Surgery Laboratory, Section of Vascular Surgery, University of Michigan Medical School, Ann Arbor, MI, USA
    J Vasc Surg 56:1089-97. 2012
    ..This study determined the vein wall response when exposed to increased and decreased plasmin activity...
  4. ncbi Urokinase plasminogen activator independent early experimental thrombus resolution: MMP2 as an alternative mechanism
    Vikram Sood
    Jobst Vascular Surgery Laboratory, Section of Vascular Surgery, University of Michigan Medical School, Ann Arbor, Michigan, USA
    Thromb Haemost 104:1174-83. 2010
    ..MMP2-dependent thrombolysis is an important compensatory mechanism of venous thrombus resolution, possibly by collagen type IV metabolism, and may represent an exploitable therapeutic avenue...
  5. pmc Critical review of mouse models of venous thrombosis
    Jose A Diaz
    Department of Surgery, Conrad Jobst Vascular Research Laboratories, University of Michigan, A570 MSRB II, Dock 6, 1150 W Medical Center Drive, Ann Arbor, MI 48109 0654, USA
    Arterioscler Thromb Vasc Biol 32:556-62. 2012
    ..In this work we review the ferric chloride model, the inferior vena cava ligation model, the inferior vena cava stenosis models, and the electrolytic inferior vena cava model and compare their advantages and disadvantages...
  6. pmc Toll-like receptor 9 signaling is critical for early experimental deep vein thrombosis resolution
    Peter K Henke
    CVC 5463, Ann Arbor, MI 48109, USA
    Arterioscler Thromb Vasc Biol 31:43-9. 2011
    ..Toll-like receptors (TLR) bridge innate immunity and host responses, including inflammation. Sterile inflammation such as a venous thrombus (Vt) may involve TLR signaling, including TLR9...
  7. pmc Postthrombotic vein wall remodeling: preliminary observations
    Kristopher B Deatrick
    Section of Vascular Surgery, Department of Surgery, University of Michigan Health System, Ann Arbor, MI, USA
    J Vasc Surg 53:139-46. 2011
    ..We sought to quantify the change in vein wall thickness in patients who fail to resolve DVT by 6 months and whether there were differences in blood or plasma levels of inflammatory proteins associated with venous remodeling...
  8. ncbi The vessel wall: A forgotten player in post thrombotic syndrome
    Scott Deroo
    Section of Vascular Surgery, Department of Surgery, University of Michigan, Ann Arbor, Michigan, USA
    Thromb Haemost 104:681-92. 2010
    ..Herein, we review what is currently known about this process with emphasis on the matrix, mediators, and vascular medial smooth muscle response after thrombotic injury. Translational therapies and potential future agents are reviewed...
  9. pmc Vein wall remodeling after deep vein thrombosis: differential effects of low molecular weight heparin and doxycycline
    Vikram Sood
    Jobst Vascular Surgery Laboratory, Section of Vascular Surgery, University of Michigan Medical School, Ann Arbor, MI, USA
    Ann Vasc Surg 24:233-41. 2010
    ..This study sought to determine the effect of exogenous MMP inhibition and its potential attenuation of early vein wall injury...
  10. ncbi Role of selectins and fibrinolysis in VTE
    Thomas W Wakefield
    Department of Surgery, Ann Arbor, MI, USA
    Thromb Res 123:S35-40. 2009
    ..In this review, we will address the role of selectins and fibrinolysis in the process of venous thrombogenesis...
  11. ncbi Mechanisms of venous thrombosis and resolution
    Thomas W Wakefield
    Section of Vascular Surgery, Department of Surgery, University of Michigan, Ann Arbor, MI 48109, USA
    Arterioscler Thromb Vasc Biol 28:387-91. 2008
    ..Knowledge of molecular and immunologic mechanisms for venous thrombosis and its resolution should allow for the future development of targeted therapies...
  12. pmc Vein wall re-endothelialization after deep vein thrombosis is improved with low-molecular-weight heparin
    Daria K Moaveni
    Jobst Vascular Surgery Laboratory, Section of Vascular Surgery, University of Michigan Medical School, Ann Arbor 48109, USA
    J Vasc Surg 47:616-24. 2008
    ..The purpose of this study was to quantify re-endothelialization after DVT and determine if low-molecular-weight heparin (LMWH) therapy affects this process...
  13. ncbi Fibrotic injury after experimental deep vein thrombosis is determined by the mechanism of thrombogenesis
    Peter K Henke
    Jobst Vascular Surgery Laboratory, Section of Vascular Surgery, University of Michigan Medical School, Ann Arbor, MI, USA
    Thromb Haemost 98:1045-55. 2007
    ..Limited stasis, non-stasis thrombosis and non-thrombotic IVC occlusion showed a lesser inflammatory response. These data suggest both a static component and the thrombus directs vein wall injury via multiple mechanisms...
  14. pmc Plasmin inhibition increases MMP-9 activity and decreases vein wall stiffness during venous thrombosis resolution
    Nicholas A Dewyer
    Jobst Vascular Surgery Laboratory, Section of Vascular Surgery, University of Michigan Medical School, Ann Arbor, Michigan, USA
    J Surg Res 142:357-63. 2007
    ..This study tested the hypothesis that pharmacological inhibition of the plasmin system would impair DVT resolution and worsen vein wall damage...