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Matrix metalloproteinases and cardiovascular disease.

The vessel wall is an integrated functional component of the circulatory system that is continually remodeling in response to hemodynamic conditions and disease states. The endothelium releases locally active mediators, such as nitric oxide and endothelin, which have immediate vasoactive properties and longer-term trophic effects on the medial SMCs. Vascular tone and compliance are determined by these SMCs, which not only actively control wall tension but also synthesize the major structural components of the vessel wall: collagens types I, III, IV, and V, elastin, proteoglycans, and glycoproteins. These components interact to form a complex network that gives blood vessels their elastic physical characteristics. Continual mechanical stresses will cause weakening of the vessel wall if the structural integrity and physical properties of the matrix are not maintained. The matrix composition determines not only the physical elastic properties of the vessel wall but also its cellular components via stored growth factors in the matrix and growth factor activation by MMPs. The matrix, therefore, rather than being merely a system of scaffolding for the surrounding cells, is a dynamic structure that is central to the control of vascular remodeling. Connective tissue repair and remodeling to maintain matrix integrity involves the synthesis and removal of these proteins, a process that depends on the action of a range of proteases and their inhibitors. Evidence suggests that there are two systems that predominate and interact to achieve homeostasis within the vessel wall: the plasminogen activator-plasmin system and the MMPs. This review focuses on discussing the increasing evidence that supports a role for enzymes of the MMP family in the pathogenesis of atherosclerosis and postangioplasty restenosis.

MMPs are a family of Zn2+- and Ca2+-dependent enzymes, which are important in the resorption of extracellular matrices in both normal physiological processes and pathological states. Nine …