title: Plasminogen activator-1 overexpression decreases experimental postthrombotic vein wall fibrosis by a non-vitronectin-dependent mechanism.
abstract: BACKGROUND
  Factors associated with postthrombotic syndrome are known clinically, but the underlying cellular processes at the vein wall are not well delineated. Prior work suggests that vein wall damage does not correlate with thrombus resolution but rather with plasminogen activator-1 (PAI-1) and matrix metalloproteinase (MMP) activity.
  
  
  OBJECTIVE
  We hypothesized that PAI-1 would confer post venous thrombosis (VT) vein wall protection via a vitronectin (Vn)-dependent mechanism.
  
  
  METHODS
  A stasis model of VT was used with harvest over 2 weeks, in wild-type, Vn(-/-) , and PAI-1-overexpressing mice (PAI-1 Tg).
  
  
  RESULTS
  PAI-1 Tg mice had larger VT at 6 and 14 days, compared to controls, but Vn(-/-) mice had no alteration of VT resolution. Gene deletion of Vn resulted in an increase in, rather than the expected decrease in, circulating PAI-1 activity. While both Vn(-/-) and PAI-1 Tg had attenuated intimal fibrosis, PAI-1 Tg had significantly less vein wall collagen and a compensatory increase in collagen III gene expression. Both Vn(-/-) and PAI-1 Tg vein wall had less monocyte chemotactic factor-1 and fewer macrophages (F4/80), with significantly less MMP-2 activity and decreased TIMP-1 antigen. Ex vivo assessment of transforming growth factor β-mediated fibrotic response showed that PAI-1 Tg vein walls had increased profibrotic gene expression (collagens I and III, MMP-2, and α-smooth muscle actin) compared with controls, opposite of the in vivo response.
  
  
  CONCLUSIONS
  The absence of Vn increases circulating PAI-1, which positively modulates vein wall fibrosis in a dose-dependent manner. Translationally, PAI-1 elevation may decrease vein wall damage after deep vein thrombosis, perhaps by decreasing macrophage-mediated activities.
authors.affiliation: Conrad Jobst Vascular Research Laboratory, Section of Vascular Surgery, Department of Surgery, University of Michigan Medical School, Ann Arbor, MI, USA.
authors.forename: A T
authors.initials: AT
authors.lastname: Obi
authors.forename: J A
authors.initials: JA
authors.lastname: Diaz
authors.forename: N L
authors.initials: NL
authors.lastname: Ballard-Lipka
authors.forename: K J
authors.initials: KJ
authors.lastname: Roelofs
authors.forename: D M
authors.initials: DM
authors.lastname: Farris
authors.forename: D A
authors.initials: DA
authors.lastname: Lawrence
authors.forename: T W
authors.initials: TW
authors.lastname: Wakefield
authors.forename: P K
authors.initials: PK
authors.lastname: Henke
mesh_terms: D000818:Animals; D004797:Enzyme-Linked Immunosorbent Assay; D005355:Fibrosis / Q000517:prevention & control; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism*; D054070:Postthrombotic Syndrome / Q000517:prevention & control*; D060888:Real-Time Polymerase Chain Reaction; D014680:Veins / Q000473:pathology*; D019096:Vitronectin / Q000235:genetics / Q000378:metabolism*
chemical_list: D017395:Plasminogen Activator Inhibitor 1; D019096:Vitronectin
keywords: PAI-1; fibrosis; postthrombotic syndrome; venous thrombosis; vitronectin