title: Multifaceted role of plasminogen activator inhibitor-1 in regulating early remodeling of vein bypass grafts.
abstract: OBJECTIVE
  The role of plasminogen activator inhibitor-1 (PAI-1) in vein graft (VG) remodeling is undefined. We examined the effect of PAI-1 on VG intimal hyperplasia and tested the hypothesis that PAI-1 regulates VG thrombin activity.
  
  
  RESULTS
  VGs from wild-type (WT), Pai1(-/-), and PAI-1-transgenic mice were implanted into WT, Pai1(-/-), or PAI-1-transgenic arteries. VG remodeling was assessed 4 weeks later. Intimal hyperplasia was significantly greater in PAI-1-deficient mice than in WT mice. The proliferative effect of PAI-1 deficiency was retained in vitronectin-deficient mice, suggesting that PAI-1's antiproteolytic function plays a key role in regulating intimal hyperplasia. Thrombin-induced proliferation of PAI-1-deficient venous smooth muscle cells (SMC) was significantly greater than that of WT SMC, and thrombin activity was significantly higher in PAI-1-deficient VGs than in WT VGs. Increased PAI-1 expression, which has been associated with obstructive VG disease, did not increase intimal hyperplasia.
  
  
  CONCLUSIONS
  Decreased PAI-1 expression (1) promotes intimal hyperplasia by pathways that do not require vitronectin and (2) increases thrombin activity in VG. PAI-1 overexpression, although it promotes SMC migration in vitro, did not increase intimal hyperplasia. These results challenge the concept that PAI-1 drives nonthrombotic obstructive disease in VG and suggest that PAI-1's antiproteolytic function, including its antithrombin activity, inhibits intimal hyperplasia.
authors.affiliation: Department of Internal Medicine and Medical Pharmacology and Physiology, University of Missouri School of Medicine, Columbia, MO, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Ji
authors.forename: Tammy L
authors.initials: TL
authors.lastname: Strawn
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Grunz
authors.forename: Meredith J
authors.initials: MJ
authors.lastname: Stevenson
authors.forename: Alexander W
authors.initials: AW
authors.lastname: Lohman
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Lawrence
authors.forename: William P
authors.initials: WP
authors.lastname: Fay
mesh_terms: D000818:Animals; D002465:Cell Movement; D049109:Cell Proliferation; D001026:Coronary Artery Bypass / Q000009:adverse effects; D005337:Fibrin / Q000378:metabolism; D005340:Fibrinogen / Q000378:metabolism; D015870:Gene Expression; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D032389:Myocytes, Smooth Muscle / Q000473:pathology / Q000502:physiology; D058426:Neointima / Q000209:etiology / Q000473:pathology / Q000503:physiopathology; D058258:Serpin E2 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D017539:Tunica Intima / Q000473:pathology; D014682:Vena Cava, Inferior / Q000473:pathology / Q000637:transplantation*; D019096:Vitronectin / Q000172:deficiency
chemical_list: D058258:Serpin E2; C511869:Serpine2 protein, mouse; D019096:Vitronectin; D005337:Fibrin; D005340:Fibrinogen