Circulation. 2003;108:1375-1381
Published online before print August 25, 2003, doi: 10.1161/01.CIR.0000086463.15540.3C
Published online before print August 25, 2003, doi: 10.1161/01.CIR.0000086463.15540.3C
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(Circulation. 2003;108:1375.)
© 2003 American Heart Association, Inc.
Basic Science Reports |
Deficiency of Gelatinase A Suppresses Smooth Muscle Cell Invasion and Development of Experimental Intimal Hyperplasia
From the Department of Geriatrics, Nagoya University Graduate School of Medicine (M.K., S.K., T.S., N.T.-M., X.W.C., T.I., A.I.), Discovery Research Laboratories, Shionogi and Co, Ltd (T.I.), Toyonaka, Osaka, and RIKEN Brain Science Institute (S.I.), Wako, Saitama, Japan.
Correspondence to Masafumi Kuzuya, MD, PhD, Department of Geriatrics, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya 466–8550, Japan. E-mail kuzuya{at}med.nagoya-u.ac.jp
Received September 5, 2002; de novo received March 12, 2003; revision received May 8, 2003; accepted May 9, 2003.
Background— Although it has been demonstrated that matrix metalloproteinases (MMPs) play an important role in the arterial remodeling in atherosclerosis and restenosis, it is not clear which MMP is involved in which process. To define the role of MMP-2 in arterial remodeling, we evaluated the influence of the targeted deletion of the MMP-2 gene on vascular remodeling after flow cessation in the murine carotid arteries.
Methods and Results— The left common carotid arteries of wild-type and MMP-2–deficient mice were ligated just proximal to their bifurcations, and the animals were then processed for morphological and biochemical studies at specific time points. MMP-2 activity and mRNA levels increased in ligated carotid arteries of wild-type mice on the basis of observation by gelatin zymography and quantitative real-time RT-PCR. There was significantly less intimal hyperplasia in MMP-2–deficient mice at 2 and 4 weeks after ligation than there in wild-type mice. Arterial explants from the aorta of MMP-2–deficient mice showed that smooth muscle cell (SMC) migration was inhibited in comparison with wild-type mice. The chemoattractant-directed invasion through a reconstituted basement membrane barrier was significantly reduced in cultured SMCs derived from MMP-2–deficient mice, although no difference was observed in SMC migration across the filter or in proliferative response between the control and MMP-2–deficient mice.
Conclusions— In a mouse carotid artery blood flow cessation model, MMP-2 contributes to intimal hyperplasia mainly through the SMC migration from the media into the intima by degrading and breaching the extracellular matrix proteins surrounding each cell and the internal elastic lamina.
Key Words: metalloproteinases • remodeling • blood flow • carotid arteries
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