Plasminogen activator inhibitor 1 and vitronectin protect against stenosis in a murine carotid artery ligation model.
OBJECTIVE
We previously reported that plasminogen activator inhibitor 1 (PAI-1), in the presence of vitronectin (VN), inhibits thrombin activity in vitro. Furthermore, we demonstrated in human atherosclerotic plaques the colocalization of thrombin, PAI-1, and VN, as well as activity of thrombin and PAI-1. Here, we show that PAI-1 is a local thrombin inhibitor in vivo.


RESULTS
We used the murine carotid artery ligation model to assess the role of PAI-1 and VN in stenosis by using PAI-1-deficient (PAI-1(-/-)) and VN(-/-) mice. Ligation resulted in a smooth muscle cell (SMC)-rich intima without infiltrating cells. We show that PAI-1(-/-) and VN(-/-) mice generate a larger intima than wild-type mice as the result of more extensive SMC proliferation, as evidenced by cell counting and staining for proliferating cell-nuclear antigen.


CONCLUSIONS
In PAI-1(-/-) mice, excessive intima formation is prevented by the thrombin-specific inhibitor hirudin. Finally, immunohistochemical analysis revealed PAI-1, VN, and (pro)thrombin antigen in intimal lesions. Our observations are compatible with inhibition of thrombin-mediated SMC proliferation by PAI-1/VN complexes.
de Waard
Vivian
V
Department of Biochemistry, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
Arkenbout
E Karin
EK
Carmeliet
Peter
P
Lindner
Volkhard
V
Pannekoek
Hans
H
D000818:Animals; D002339:Carotid Arteries / Q000601:surgery; D016893:Carotid Stenosis / Q000378:metabolism* / Q000517:prevention & control*; D002455:Cell Division / Q000502:physiology; D003238:Connective Tissue / Q000737:chemistry; D004195:Disease Models, Animal; D006629:Hirudins / Q000494:pharmacology; D007150:Immunohistochemistry; D008026:Ligation / Q000379:methods; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000166:cytology; D017395:Plasminogen Activator Inhibitor 1 / Q000172:deficiency / Q000276:immunology / Q000378:metabolism / Q000502:physiology*; D011516:Prothrombin / Q000276:immunology / Q000378:metabolism; D017539:Tunica Intima / Q000737:chemistry / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D017540:Tunica Media / Q000737:chemistry; D019096:Vitronectin / Q000172:deficiency / Q000276:immunology / Q000378:metabolism / Q000502:physiology*
D006629:Hirudins; D017395:Plasminogen Activator Inhibitor 1; D019096:Vitronectin; D011516:Prothrombin