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 n eointimal 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 expres sion 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, G M 6001, was administered to rats for various times after balloon injur y 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+/-0.008 mm(2) compared with 0.095+/- 0.01 mm(2) in the control group. Neither intimal nor medial SMC replic ation rates were decreased by GM 6001 treatment, supporting our hypoth esis that the decrease in lesion size was due to inhibition of MMP-med iated migration and not inhibition of replication. By 14 days after in jury, however, intimal area and SMC number were the same in control an d inhibitor-treated rats. An increased rare of SMC replication in the GM 6001 rats (replication rates at 10 days were 56.7+/-10.0% in the GM 6001 group and 16.97+/-1.73% in the control group) contributed to ''c atch-up'' growth of the neointima. Thus, it appears that inhibiting SM C migration with MMP inhibitors is not sufficient to inhibit lesion gr owth, and lesion size eventually catches up to control via increased S MC replication.