title: The effect of matrix metalloproteinase 2 and matrix metalloproteinase 2/9 deletion in experimental post-thrombotic vein wall remodeling.
abstract: BACKGROUND
  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.
  
  
  METHODS
  Stasis VT was produced by ligation of the inferior vena cava and tissue was harvested at 2, 8, and 21 days in MMP2 -/- and genetic wild type (WT) mice. Tissue analysis by immunohistochemistry, enzyme-linked immunosorbent assay, real-time polymerase chain reaction, and zymography was performed.
  
  
  RESULTS
  Thrombus resolution was less at 8 days in MMP2 -/- compared with WT, evidenced by a 51% increase in VT size (P < .01), and threefold fewer von Willebrand's factor positive channels (P < .05). In MMP2 -/- mice, the main phenotypic fibrotic differences occurred at 8 days post-VT, with significantly less vein wall collagen content (P = .013), fourfold lower procollagen III gene expression (P < .01), but no difference in procollagen I compared with WT. Decreased inflammation in MMP2 -/- vein walls was suggested by ∼ threefold reduced TNFα and IL-1β at 2 days and 8 days post-VT (P < .05). A fourfold increase in vein wall monocytes (P = .03) with threefold decreased apoptosis (P < .05), but no difference in cellular proliferation at 8 days was found in MMP2 -/- compared with WT. As increased compensatory MMP9 activity was observed in the MMP2 -/-mice, MMP2/9 double null mice had thrombus induced with VT harvest at 8 days. Consistently, twofold larger VT, a threefold decrease in vein wall collagen, and a threefold increase in monocytes were found (all P < .05). Similar findings were observed in MMP9 -/- mice administered an exogenous MMP2 inhibitor.
  
  
  CONCLUSIONS
  In stasis VT, deletion of MMP2 was associated with less midterm vein wall fibrosis and inflammation, despite an increase in monocytes. Consideration that VT resolution was impaired with MMP2 (and MMP2/9) deletion suggests direct inhibition will likely also require anticoagulant therapy.
authors.affiliation: Conrad Jobst Vascular Research Laboratory, Section of Vascular Surgery, Department of Surgery, University of Michigan Medical School, Ann Arbor, Mich.
authors.forename: Kristopher B
authors.initials: KB
authors.lastname: Deatrick
authors.forename: Catherine E
authors.initials: CE
authors.lastname: Luke
authors.forename: Megan A
authors.initials: MA
authors.lastname: Elfline
authors.forename: Vikram
authors.initials: V
authors.lastname: Sood
authors.forename: Joseph
authors.initials: J
authors.lastname: Baldwin
authors.forename: Gilbert R
authors.initials: GR
authors.lastname: Upchurch
authors.forename: Farouc A
authors.initials: FA
authors.lastname: Jaffer
authors.forename: Thomas W
authors.initials: TW
authors.lastname: Wakefield
authors.forename: Peter K
authors.initials: PK
authors.lastname: Henke
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D005355:Fibrosis; D017353:Gene Deletion; D005786:Gene Expression Regulation; D005838:Genotype; D018836:Inflammation Mediators / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D008026:Ligation; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000172:deficiency* / Q000235:genetics; D020780:Matrix Metalloproteinase 9 / Q000172:deficiency* / Q000235:genetics; D061965:Matrix Metalloproteinase Inhibitors / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009000:Monocytes / Q000473:pathology; D010641:Phenotype; D011347:Procollagen / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014682:Vena Cava, Inferior / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology / Q000601:surgery; D020246:Venous Thrombosis / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D014841:von Willebrand Factor / Q000378:metabolism
chemical_list: D018836:Inflammation Mediators; D053583:Interleukin-1beta; D061965:Matrix Metalloproteinase Inhibitors; D011347:Procollagen; D014409:Tumor Necrosis Factor-alpha; D014841:von Willebrand Factor; D020778:Matrix Metalloproteinase 2; C522362:Mmp2 protein, mouse; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse