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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2002;22:934.)
© 2002 American Heart Association, Inc.

Vascular Biology

Endogenous Vitronectin and Plasminogen Activator Inhibitor-1 Promote Neointima Formation in Murine Carotid Arteries

Lin Peng; Nitin Bhatia; Andrew C. Parker; Yanhong Zhu; William P. Fay

From the Department of Internal Medicine, University of Michigan Medical School, Ann Arbor.

Correspondence to William P. Fay, MD, University of Michigan Medical Center, 7301 MSRB III, 1150 W Medical Center Dr, Ann Arbor, MI 48109-0644. E-mail wfay{at}umich.edu

Abstract— We examined the roles of vitronectin and plasminogen activator inhibitor-1 (PAI-1) in neointima development. Neointima formation after carotid artery ligation or chemical injury was significantly greater in wild-type mice than in vitronectin-deficient (Vn^-/-) mice. Vascular smooth muscle cell (VSMC) proliferation did not differ between groups, suggesting that vitronectin promoted neointima development by enhancing VSMC migration. Neointima formation was significantly attenuated in PAI-1–deficient (PAI-1^-/-) mice compared with control mice. Because intravascular fibrin may function as a provisional matrix for invading VSMCs, we examined potential mechanisms by which vitronectin and PAI-1 regulate fibrin stability and fibrin-VSMC interactions. Inhibition of activated protein C by PAI-1 was markedly attenuated in vitronectin-deficient plasma. The capacity of PAI-1 to inhibit clot lysis was significantly attenuated in vitronectin-deficient plasma, and this effect was not explained simply by the PAI-1–stabilizing properties of vitronectin. The adhesion and spreading of VSMCs were significantly greater on wild-type plasma clots and PAI-1–deficient plasma clots than on vitronectin-deficient plasma clots. We conclude that endogenous levels of vitronectin and PAI-1 enhance neointima formation in response to vascular occlusion or injury. Their effects may be mediated to a significant extent by their capacity to promote intravascular fibrin deposition and by the capacity of vitronectin to enhance VSMC-fibrin interactions.

Key Words: vitronectin • plasminogen activator inhibitor-1 • vascular smooth muscle cells • neointima • vascular biology

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