Injury Induces Dedifferentiation of Smooth Muscle Cells and Increased Matrix-Degrading Metalloproteinase Activity in Human Saphenous Vein

Abstract

Abstract-Long-term patency of human saphenous vein bypass grafts is low because of intimal thickening and superimposed atherosclerosis. Matrix-degrading metalloproteinases (MMPs) and changes in vascular smooth muscle cell (VSMC) phenotype are thought to be essential for the VSMC migration that contributes to intimal thickening. We examined VSMC phenotype and MMP activity in saphenous veins obtained before and after surgical manipulation. Surgical preparation 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 gelatinolytic activities measured by in situ zymography were dramatically elevated by injury. The expression of desmin and smoothelin was significantly decreased by injury, whereas vimentin expression was significantly increased. In addition, these changes in phenotype and MMP activity were localized to a subpopulation of VSMCs, the circumferential medial VSMCs. Our data show that surgical 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 thickening that leads to graft failure. Medial VSMCs exist in the normal blood vessel wall in the contractile (differentiated) phenotype. These have a "spindlelike" morphology, maintain vessel wall tone, and are rich in contractile and intermediate filament proteins (IFPs). It has been suggested that migrating and proliferating VSMCs have dedifferentiated to a synthetic phenotype, characterized by a reduction in contractile proteins and alterations in IFPs (see review by Owens 5 ). Recent studies illustrate that the amounts of the IFPs vimentin and desmin, the cytoskeleton-related protein smoothelin, and the contractile proteins ␣-smooth muscle (SM) actin, SM myosin heavy chain (SMMHC), and tropomyosin change when VSMCs shift from the contractile to the synthetic phenotype. [5][6][7] Mechanical injury to the blood vessel wall, particularly endothelial damage, is thought to trigger phenotypic modulation of medial VSMCs, shifting them toward the synthetic phenotype (see reviews by Thyberg and colleagues 8 -10 ). To enable VSMC migration, remodeling of the basement membrane and of the interstitial collagenous matrix that maintains VSMCs in a quiescent state must occur. 11 Mechanical injury of aortic explants 12 and isolated VSMCs 13 stimulates the production of extracellular matrix-degrading metalloproteinases (MMPs), which are mainly associated with VSMCs of the synthetic phenotype. 14,15 Injury of rat carotid arteries 16 and human saphenous veins 17 increases the expression of basement membrane-degrading MMP-2 and MMP-9. Furthermore, MMP inhibitors,12,[18][19][20] as well as gene transfer of the endogenous tissue inhibitors of MMPs (TIMPs), [21][22][23][24][25] have demonstrated the involvement of MMPs in injury-stimulated intimal thickening. Injury also...

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