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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2009;29:1565.)
© 2009 American Heart Association, Inc.

Integrative Physiology/Experimental Medicine

Recombinant Plasminogen Activator Inhibitor-1 Inhibits Intimal Hyperplasia

Jianbo Wu; Lin Peng; Grainne A. McMahon; Daniel A. Lawrence; William P. Fay

From the Departments of Internal Medicine and Medical Pharmacology & Physiology (J.W., L.P., W.P.F.), University of Missouri School of Medicine, and Research Service, Harry S. Truman Memorial Veterans Affairs Hospital, Columbia; and the Department of Internal Medicine (G.A.M., D.A.L.), University of Michigan Medical School, Ann Arbor.

Correspondence to Jianbo Wu, MD, PhD, University of Missouri, 5 Hospital Drive, CE344-DC095.00, Columbia, MO 65212. E-mail wuji{at}health.missouri.edu

Objective— Plasminogen activator inhibitor-1 (PAI-1) overexpression is implicated in vascular disease. However, the effects of a primary increase in PAI-1 expression on arterial remodeling are poorly defined. We tested the hypothesis that recombinant PAI-1 inhibits intimal hyperplasia after vascular injury.

Methods and Results— Rats underwent carotid artery injury and received intraperitoneal injections of saline or mutant forms of PAI-1 for 14 days, including an active stable mutant (PAI-1-14-1b), a mutant lacking anti-PA activity (PAI-1-R), or a mutant defective in vitronectin (VN) binding (PAI-1-K). All forms of PAI-1 significantly inhibited neointima formation, whereas elastase-cleaved PAI-1, which lacks both anti-PA and VN-binding functions, did not. Similar effects were observed in a murine model. However, the antiproliferative effect of PAI-1-R was lost in Vn^–/– mice, suggesting that PAI-1 can inhibit intimal hyperplasia in vivo by a VN-dependent pathway not involving direct inhibition of proteases. In vitro, recombinant PAI-1 inhibited wild-type vascular smooth muscle cell (VSMC) proliferation, promoted apoptosis, and inhibited migration. These effects were lost in VN-deficient VSMCs.

Conclusion— Recombinant PAI-1 inhibits intimal hyperplasia by inhibiting proteases and binding VN. VN is a key determinant of the antiproliferative effect of PAI-1 overexpression. PAI-1-R has therapeutic potential to inhibit vascular restenosis without promoting thrombosis.

Recombinant plasminogen activator inhibitor-1 (PAI-1), including mutant forms incapable of inhibiting fibrinolysis, inhibited intimal hyperplasia after mechanical injury in rodents. The effect of PAI-1 overexpression on arterial remodeling was critically dependent on VN expression, both in vivo and in vitro.

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