EXTRACELLULAR-MATRIX DEGRADING METALLOPROTEINASES IN THE PATHOGENESISOF ARTERIOSCLEROSIS

We review the importance of extracellular matrix remodelling to the pr ocesses of vascular smooth muscle cell migration and proliferation tha t contribute to morphogenesis of the atherosclerotic plaque. In partic ular, the role of the matrix degrading metalloproteinase (MMP) family is discussed. This family of neutral, Zn2+-requiring enzymes are capab le, in principle, of degrading all matrix proteins. Their activity is tightly controlled, however, at the level of snythesis of the inactive zymogens, activation by limited proteolysis and binding to endogenous inhibitor proteins (TIMPs). Direct evidence is presented for the invo lvement of MMPs in proliferation and outgrowth of vascular smooth musc le cells from explants of rabbit aorta in vitro. This was obtained usi ng two structurally-unrelated inhibitors of MMPs, Ro 31-4724 and Ro 31 -7467, both of which inhibited proliferation of cells in a concentrati on-dependent manner, Ro 31-4724 also inhibited outgrowth. Rabbit aorti c 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 31-7 467. The evidence suggests that degradation of basement membrane by ge latinase is required for proliferation and outgrowth of these cells. T he implications of these findings for the pathogenesis and treatment o f atherosclerosis are also discussed.