The most common sequela of deep vein thrombosis (DVT) is post thrombotic syndrome (PTS). This is a significantly morbid disease that results from vein wall injury secondary to the inflammatory response of the lysing thrombus. Post DVT vein wall remodeling resembles many diseases that are characterized by chronic irreversible fibrotic changes. The chemokine SLC (CCL21) and its primary receptor, CCR7, have been shown to be integral in both human and experimental fibrotic organ injury. In conjunction with our preliminary data, we believe the SLC-CCR7 axis is critical to DVT resolution and pathological vein wall injury response. In this proposal we test the overall hypothesis that SLC, via CCR7 signaling, mediates vein wall fibrotic injury after DVT. This will be addressed by three Specific Aims. I: To define the role of thrombogenic injury on vein wall SLC-CCR7 expression;II: To determine the effect and mechanism of SLC on post-DVT vein wall cellular matrix protein production, proliferation, and proteinase activity, and the contribution of SLC to endothelial to mesenchymal transformation after DVT;III: To demonstrate that bone marrow derived CCR7 positive cells directly mediate vein wall fibrotic injury after DVT, and that currently available therapies and anti- CCR7 strategies can reverse early fibrotic injury. The current proposal will elucidate the role of SLC, and its effector cell, the CCR7 positive leukocyte, on vein wall remodeling by several mechanisms of thrombotic injury in the mouse, and by in vitro vein wall cellular analysis. The long-term goal of this study is to define the basic mechanisms of post DVT vein wall fibrotic injury with the translation to human medical therapies to: 1) accelerate DVT resolution without anticoagulation risks: 2) to reduce vein wall fibrotic injury and thus reduce the incidence of PTS.

Public Health Relevance

This proposal will establish the role of a chemokine that mediates a circulating wound healing cell in vein wall remodeling after deep vein thrombosis. The long term goal is to define a therapy to decrease post thrombotic syndrome, a common and morbid complication of deep vein thrombosis.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL092129-03
Application #
8021841
Study Section
Atherosclerosis and Inflammation of the Cardiovascular System Study Section (AICS)
Program Officer
Link, Rebecca P
Project Start
2009-04-01
Project End
2013-02-28
Budget Start
2011-03-01
Budget End
2012-02-29
Support Year
3
Fiscal Year
2011
Total Cost
$386,250
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Surgery
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
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Dewyer, Nicholas A; El-Sayed, Osama M; Luke, Catherine E et al. (2015) Divergent effects of Tlr9 deletion in experimental late venous thrombosis resolution and vein wall injury. Thromb Haemost 114:1028-37
Obi, Andrea T; Diaz, Jose A; Ballard-Lipka, Nicole L et al. (2014) Low-molecular-weight heparin modulates vein wall fibrotic response in a plasminogen activator inhibitor 1-dependent manner. J Vasc Surg Venous Lymphat Disord 2:441-450.e1
Obi, A T; Diaz, J A; Ballard-Lipka, N L et al. (2014) Plasminogen activator-1 overexpression decreases experimental postthrombotic vein wall fibrosis by a non-vitronectin-dependent mechanism. J Thromb Haemost 12:1353-63
Laser, Adriana; Elfline, Megan; Luke, Cathy et al. (2014) Deletion of cysteine-cysteine receptor 7 promotes fibrotic injury in experimental post-thrombotic vein wall remodeling. Arterioscler Thromb Vasc Biol 34:377-85
Deatrick, Kristopher B; Luke, Catherine E; Elfline, Megan A et al. (2013) The effect of matrix metalloproteinase 2 and matrix metalloproteinase 2/9 deletion in experimental post-thrombotic vein wall remodeling. J Vasc Surg 58:1375-1384.e2
Deatrick, Kristopher B; Obi, Andrea; Luke, Catherine E et al. (2013) Matrix metalloproteinase-9 deletion is associated with decreased mid-term vein wall fibrosis in experimental stasis DVT. Thromb Res 132:360-6
Diaz, Jose A; Obi, Andrea T; Myers Jr, Daniel D et al. (2012) Critical review of mouse models of venous thrombosis. Arterioscler Thromb Vasc Biol 32:556-62
Baldwin, Joe F; Sood, Vikram; Elfline, Megan A et al. (2012) The role of urokinase plasminogen activator and plasmin activator inhibitor-1 on vein wall remodeling in experimental deep vein thrombosis. J Vasc Surg 56:1089-97
Henke, Peter K; Mitsuya, Mayo; Luke, Catherine E et al. (2011) Toll-like receptor 9 signaling is critical for early experimental deep vein thrombosis resolution. Arterioscler Thromb Vasc Biol 31:43-9

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