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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2002;22:499.)
© 2002 American Heart Association, Inc.

Thrombosis

Lack of Plasminogen Activator Inhibitor-1 Promotes Growth and Abnormal Matrix Remodeling of Advanced Atherosclerotic Plaques in Apolipoprotein E–Deficient Mice

Aernout Luttun; Florea Lupu; Erik Storkebaum; Marc F. Hoylaerts; Lieve Moons; James Crawley; Françoise Bono; A. Robin Poole; Peter Tipping; Jean-Marc Herbert; Désiré Collen; Peter Carmeliet

From the Center for Transgene Technology and Gene Therapy (A.L., E.S., M.F.H., L.M., D.C., P.C.), Flanders Interuniversity Institute for Biotechnology, Leuven, Belgium; Cardiovascular Biology Research Program (F.L., J.C.), Oklahoma Medical Research Foundation, Oklahoma City; the Cardiovascular/Thrombosis Research Department (F.B., J.-M.H.), Sanofi-Synthélabo, Toulouse, France; Joint Diseases Laboratory (A.R.P.), Shriners Hospitals for Children, McGill University, Montreal, Quebec, Canada; and the Center for Inflammatory Diseases (P.T.), Monash University Medical Center, Clayton, Victoria, Australia.

Correspondence to P. Carmeliet, MD, PhD, Center for Transgene Technology and Gene Therapy, Campus Gasthuisberg, Herestraat 49, University of Leuven, Leuven, B-3000, Belgium. E-mail peter.carmeliet{at}med.kuleuven.ac.be

Epidemiological studies suggest that elevated plasma levels of plasminogen activator inhibitor-1 (PAI-1) predispose an individual to ischemic heart disease or promote plaque progression by inhibiting fibrinolysis. In the present study, loss of PAI-1 in apolipoprotein E (apoE)-deficient (apoE^-/-:PAI-1^-/-) mice promoted the growth of advanced atherosclerotic plaques, which was due to enhanced extracellular matrix deposition. ApoE^-/-:PAI-1^-/- plaques also exhibited collagen fiber disorganization and degradation. Immunostaining and bone marrow transplantation revealed that smooth muscle cells, not macrophages, primarily expressed PAI-1 in plaques. Thus, although PAI-1 may promote plaque growth because of its antifibrinolytic properties, the present study reveals a protective role for PAI-1 by limiting plaque growth and preventing abnormal matrix remodeling.

Key Words: plasminogen activator inhibitor-1 • atherosclerosis • collagen • matrix • transforming growth factor-ß1

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