© 1999 American Heart Association, Inc.
Integrative Physiology |
Matrix Metalloproteinase-9 Overexpression Enhances Vascular Smooth Muscle Cell Migration and Alters Remodeling in the Injured Rat Carotid Artery
From the Division of Vascular Surgery, (D.P.M., R.D.K., D.H., S.M.H., A.W.C.), Department of Surgery, and Department of Pathology (D.F.B.-P., R.A.S., S.C.), University of Washington, Seattle, Wash.
Correspondence to Alexander W. Clowes, MD, Division of Vascular Surgery, Department of Surgery, University of Washington School of Medicine, HSB BB442, Box 356410, 1959 NE Pacific St, Seattle, WA 98195-6410. E-mail clowes{at}u.washington.edu
Abstract—Matrix metalloproteinase-9 (MMP-9) has been implicated in the pathogenesis of atherosclerosis as well as intimal hyperplasia after vascular injury. We used Fischer rat smooth muscle cells (SMCs) overexpressing MMP-9 to determine the role of MMP-9 in migration and proliferation as well as in vessel remodeling after balloon denudation. Fischer rat SMCs were stably transfected with a cDNA for rat MMP-9 under the control of a tetracycline-regulatable promoter. In this system, MMP-9 was overexpressed in the absence, but not in the presence, of tetracycline. In vitro SMC migration was determined using a collagen invasion assay as well as a Boyden chamber assay. In vivo migration was determined by measuring the invasion into the medial and intimal layers of transduced SMCs seeded on the outside of the artery. Transduced SMCs were also seeded on the luminal surface, and the effect of local MMP-9 overexpression on vascular structure was measured morphometrically at intervals up to 28 days. MMP-9 overexpression enhanced SMC migration in both the collagen invasion assay and Boyden chamber in vitro, increased SMC migration into an arterial matrix in vivo, and altered vessel remodeling by increasing the vessel circumference, thinning the vessel wall and decreasing intimal matrix content. These results demonstrate that MMP-9 enhances vascular SMC migration in vitro and in vivo and alters postinjury vascular remodeling.
Key Words: matrix metalloproteinase-9 • migration • rat • smooth muscle cell • remodeling
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