Recombinant plasminogen activator inhibitor-1 inhibits intimal hyperplasia.
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.


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.


CONCLUSIONS
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.
Wu
Jianbo
J
Department of Internal Medicine, University of Missouri School of Medicine, and Research Service, Harry S. Truman Memorial Veterans Affairs Hospital, Columbia, MO 65212, USA. wuji@health.missouri.edu
Peng
Lin
L
McMahon
Grainne A
GA
Lawrence
Daniel A
DA
Fay
William P
WP
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002339:Carotid Arteries / Q000187:drug effects / Q000473:pathology; D002465:Cell Movement; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D006965:Hyperplasia; D026503:Low Density Lipoprotein Receptor-Related Protein-1 / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects; D032389:Myocytes, Smooth Muscle / Q000502:physiology; D017395:Plasminogen Activator Inhibitor 1 / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000494:pharmacology; D017539:Tunica Intima / Q000187:drug effects* / Q000473:pathology; D019096:Vitronectin / Q000502:physiology*
D026503:Low Density Lipoprotein Receptor-Related Protein-1; D017395:Plasminogen Activator Inhibitor 1; D011994:Recombinant Proteins; D019096:Vitronectin