Deficiency of gelatinase a suppresses smooth muscle cell invasion and development of experimental intimal hyperplasia.
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.


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.
Kuzuya
Masafumi
M
Department of Geriatrics, Nagoya University Graduate School of Medicine, Toyonaka, Nagoya 466-8550, Japan. kuzuya@med.nagoya-u.ac.jp
Kanda
Shigeru
S
Sasaki
Takeshi
T
Tamaya-Mori
Norika
N
Cheng
Xian Wu
XW
Itoh
Takeshi
T
Itohara
Shigeyoshi
S
Iguchi
Akihisa
A
D000818:Animals; D002339:Carotid Arteries / Q000201:enzymology / Q000473:pathology / Q000601:surgery; D016893:Carotid Stenosis / Q000201:enzymology / Q000209:etiology* / Q000473:pathology; D002465:Cell Movement; D002478:Cells, Cultured; D006965:Hyperplasia; D007150:Immunohistochemistry; D007700:Kinetics; D008026:Ligation; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000502:physiology*; D017539:Tunica Intima / Q000473:pathology
D020778:Matrix Metalloproteinase 2