Plasminogen activator inhibitor-1 and vitronectin promote vascular thrombosis in mice.
Occlusive thrombosis depends on the net balance between platelets, coagulation, and fibrinolytic factors. Epidemiologic information suggests that plasminogen activator inhibitor-1 (PAI-1), a central regulator of the fibrinolytic system, plays an important role in determining the overall risk for clinically significant vascular thrombosis. Vitronectin (VN), an abundant plasma and matrix glycoprotein, binds PAI-1 and stabilizes its active conformation. This study assessed the role of PAI-1 and VN expression in the formation of occlusive vascular thrombosis following arterial or venous injury. The common carotid arteries of 17 wild-type (WT) mice and 8 mice deficient in PAI-1 were injured photochemically while blood flow was continuously monitored. WT mice developed occlusive thrombi at 52.0 +/- 3.8 minutes (mean +/- SEM) following injury; mice deficient in PAI-1 developed occlusive thrombosis at 127 +/- 15 minutes (P <.0001). Mice deficient in VN (n = 12) developed vascular occlusion 77 +/- 11 minutes after injury, intermediate between the values observed for WT mice (P <.03) and mice deficient in PAI-1 (P <.01). PAI-1 and VN also affected the time to occlusion after injury to the jugular vein. Three WT mice developed occlusive venous thrombosis an average of 39.7 +/- 1 minutes following the onset of injury, whereas the jugular veins of 4 mice deficient in PAI-1 and 4 deficient in VN occluded 56.7 +/- 5 and 58.7 +/- 2 minutes, respectively, following injury (P <.04 and P <.01 compared to WT mice). These results suggest that endogenous fibrinolysis and its regulation by PAI-1 and VN have important roles in the development of occlusive vascular thrombosis after vascular injury. (Blood. 2000;95:577-580)
Eitzman
D T
DT
Cardiovascular Research Center and Division of Molecular Medicine and Human Genetics, Department of Internal Medicine, and the Howard Hughes Medical Institute, University of Michigan Medical Center, Ann Arbor, MI 49109-0644, USA. deitzman@umich.edu
Westrick
R J
RJ
Nabel
E G
EG
Ginsburg
D
D
D000818:Animals; D016893:Carotid Stenosis / Q000097:blood / Q000235:genetics / Q000503:physiopathology*; D007601:Jugular Veins; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017395:Plasminogen Activator Inhibitor 1 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D013927:Thrombosis / Q000097:blood / Q000235:genetics / Q000503:physiopathology*; D020246:Venous Thrombosis / Q000097:blood / Q000235:genetics / Q000503:physiopathology*; D019096:Vitronectin / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
D017395:Plasminogen Activator Inhibitor 1; D019096:Vitronectin