on October 17, 2002
Published online before print October 17, 2002, doi: 10.1161/01.ATV.0000042231.04318.E6
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Submitted on August 9, 2002
Accepted on September 24, 2002
Plasminogen Activator Inhibitor 1 and Vitronectin Protect Against Stenosis in a Murine Carotid Artery Ligation Model
Vivian de Waard ;
From the Department of Biochemistry (V.d.W., E.K.A., H.P.), Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; Center for Transgene Technology and Gene Therapy (P.C.), Flanders Interuniversity Institute for Biotechnology, Leuven, Belgium; and Maine Medical Center Research Institute (V.L.), Scarborough, Me.
* To whom correspondence should be addressed. E-mail: h.pannekoek{at}amc.uva.nl.
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.
Methods and 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.
Key words: restenosis • smooth muscle cells • plasminogen activator inhibitor 1 • vitronectin • thrombin
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