Published online before print August 12, 2004, doi: 10.1161/01.ATV.0000141840.27300.fd
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© 2004 American Heart Association, Inc.
Atherosclerosis and Lipoproteins |
Compensatory Vascular Remodeling During Atherosclerotic Lesion Growth Depends on Matrix Metalloproteinase-9 Activity
From the Coulter Department of Biomedical Engineering (S.M.L., Z.S.G.) and the Department of Medicine (D.E.M.), Emory University School of Medicine, Atlanta, Ga.
Correspondence to Dr Susan M. Lessner, Emory University School of Medicine, Coulter Department of Biomedical Engineering, WMB 2001, 101 Woodruff Circle, Atlanta, GA 30322. E-mail slessne{at}emory.edu
Objective— The compensatory arterial remodeling associated with atherosclerotic plaques is thought to rely on the activity of matrix metalloproteinases (MMP). To assess the role of MMP-9, we analyzed the effect of MMP-9 genetic deficiency on the development and remodeling of experimental atherosclerotic lesions induced in the apolipoprotein E (apoE) knockout (–/–) mouse model.
Methods and Results— We analyzed remodeling parameters and cellular composition of experimental carotid artery atherosclerotic lesions in apoE–/– and apoE–/– MMP-9–/– double-knockout (DKO) mice at 0, 3, 7, and 14 days after induction by flow cessation. Morphometric image analysis of arterial tissue sections indicated that overall artery size, measured as area encompassed by the external elastic lamina, increased 3.1-fold in the apoE–/– mice but only 1.6-fold in the DKO mice (P<0.0001) by 14 days. At the same time, the net lesion area occupied by macrophages was similar. Statistical analysis indicated that the overall expansion of the artery was 2.5-fold less sensitive to macrophage content in DKO compared with apoE–/– mice. No compensatory increase in other gelatinolytic activities was detected in the DKO.
Conclusions— MMP-9 deficiency significantly impaired compensatory vessel enlargement during carotid artery lesion development in the apoE–/– mouse, without altering macrophage content of lesions.
MMP-9 deficiency impairs the compensatory outward remodeling during carotid lesion development in an apoE–/– mouse model of atherosclerosis without significantly altering neointimal macrophage accumulation. Arterial expansion becomes relatively insensitive to lesion macrophage content in the absence of MMP-9.
Key Words: matrix metalloproteinases • vascular remodeling • atherosclerosis • macrophages • transgenic mouse models
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