Injury induces dedifferentiation of smooth muscle cells and increased matrix-degrading metalloproteinase activity in human saphenous vein

Long-term patency of human saphenous vein bypass grafts is low because of i ntimal thickening and superimposed atherosclerosis. Matrix-degrading metall oproteinases (MMPs) and changes in vascular smooth muscle cell (VSMC) pheno type are thought to be essential for the VSMC migration that contributes to intimal thickening. We examined VSMC phenotype and MMP activity in sapheno us veins obtained before and after surgical manipulation Surgical preparati on of the veins significantly increased pro-MMP-1 expression by 2-fold and significantly reduced tissue inhibitor of MMPs (TIMP)-2 expression, whereas MMP-3 and TIMP-1 were unaffected. Furthermore, caseinolytic and gelatinoly tic activities measured by in situ zymography were dramatically elevated by injury. The expression of desmin and smoothelin was significantly decrease d by injury, whereas vimentin expression was significantly increased. In ad dition, these changes in phenotype and MMP activity were localized to a sub population of VSMCs, the circumferential medial VSMCs. Our data show that s urgical preparative injury induces phenotypic modulation of a subpopulation of medial VSMCs to a synthetic phenotype and increases MMP activity. This may favor matrix degradation, VSMC migration, and the subsequent intimal th ickening that leads to graft failure.