Endogenous vitronectin and plasminogen activator inhibitor-1 promote neointima formation in murine carotid arteries.
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.
Peng
Lin
L
Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, USA.
Bhatia
Nitin
N
Parker
Andrew C
AC
Zhu
Yanhong
Y
Fay
William P
WP
D000818:Animals; D002339:Carotid Arteries / Q000503:physiopathology / Q000601:surgery; D020212:Carotid Artery Injuries / Q000139:chemically induced; D002460:Cell Line; D002465:Cell Movement / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000196:embryology / Q000503:physiopathology; D018919:Neovascularization, Physiologic / Q000235:genetics / Q000502:physiology*; D017395:Plasminogen Activator Inhibitor 1 / Q000172:deficiency / Q000378:metabolism / Q000502:physiology*; D051381:Rats; D017539:Tunica Intima / Q000503:physiopathology*; D019096:Vitronectin / Q000172:deficiency / Q000378:metabolism / Q000502:physiology*
D017395:Plasminogen Activator Inhibitor 1; D019096:Vitronectin