Extracellular matrix degrading metalloproteinases in the pathogenesis of arteriosclerosis

We review the importance of extracellular matrix remodelling to the processes of vascular smooth muscle cell migration and proliferation that contribute to morphogenesis of the atherosclerotic plaque. In particular, the role of the matrix degrading metalloproteinase (MMP) family is discussed. This family of neutral, ZN(2+)-requiring enzymes are capable, in principle, of degrading all matrix proteins. Their activity is tightly controlled, however, at the level of synthesis of the inactive zymogens, activation by limited proteolysis and binding to endogenous inhibitor proteins (TIMPs). Direct evidence is presented for the involvement of MMPs in proliferation and outgrowth of vascular smooth muscle cells from explants of rabbit aorta in vitro. This was obtained using two structurally-unrelated inhibitors of MMPs, Ro 31-4724 and Ro 31-7467, both of which inhibited proliferation of cells in a concentration-dependent manner, Ro 31-4724 also inhibited outgrowth. Rabbit aortic smooth muscle cells were further shown to release MMPs, namely a 95 and a 72 kDa gelatinases that were inhibited by Ro 31-4724 and Ro 31-7467. The evidence suggests that degradation of basement membrane by gelatinase is required for proliferation and outgrowth of these cells. The implications of these findings for the pathogenesis and treatment of atherosclerosis are also discussed.