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Inhibition of Matrix Metalloproteinase Activity Inhibits Smooth Muscle Cell Migration but Not Neointimal Thickening After Arterial Injury
Smooth muscle cell (SMC) migration and replication are important for neointimal formation after arterial injury. Migration of SMCs requires degradation of basement membrane and extracellular matrix surrounding the cell, and our previous work has shown a correlation between expression of two matrix-d...
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Published in: | Circulation research 1996-01, Vol.78 (1), p.38-43 |
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Main Authors: | , , |
Format: | Article |
Language: | English |
Subjects: | |
Citations: | Items that this one cites Items that cite this one |
Online Access: | Get full text |
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Summary: | Smooth muscle cell (SMC) migration and replication are important for neointimal formation after arterial injury. Migration of SMCs requires degradation of basement membrane and extracellular matrix surrounding the cell, and our previous work has shown a correlation between expression of two matrix-degrading metalloproteinases (MMPs), MMP-2 and MMP-9, and smooth muscle migration into the intima in the balloon catheter-injured rat carotid artery. In the present study, an MMP inhibitor, GM 6001, was administered to rats for various times after balloon injury of the carotid artery. Inhibition of MMP activity resulted in a 97% decrease in the number of SMCs that migrated into the intima by 4 days after injury, and lesion growth was retarded by continuous treatment with GM 6001 for up to 10 days after injury. At 10 days, intimal area in GM 6001-treated rats was 0.035 plus minus 0.008 mm compared with 0.095 plus minus 0.01 mm in the control group. Neither intimal nor medial SMC replication rates were decreased by GM 6001 treatment, supporting our hypothesis that the decrease in lesion size was due to inhibition of MMP-mediated migration and not inhibition of replication. By 14 days after injury, however, intimal area and SMC number were the same in control and inhibitor-treated rats. An increased rate of SMC replication in the GM 6001 rats (replication rates at 10 days were 56.7 plus minus 10.0% in the GM 6001 group and 16.97 plus minus 1.73% in the control group) contributed to ``catch-up'' growth of the neointima. Thus, it appears that inhibiting SMC migration with MMP inhibitors is not sufficient to inhibit lesion growth, and lesion size eventually catches up to control via increased SMC replication.(Circ Res. 1996;78:38-43.) |
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ISSN: | 0009-7330 1524-4571 |
DOI: | 10.1161/01.RES.78.1.38 |