DEVELOPMENT-RELATED CHANGES IN MATRIX METALLOPROTEINASE EXPRESSION INHUMAN AORTIC SMOOTH-MUSCLE CELLS

BACKGROUND: It is known that extracellular matrix-degrading enzymes pl ay an important role in tissue remodeling and that large amounts of st ructural proteins including types I, III, IV, and V collagens and elas tin are produced by smooth muscle cells (SMC) in the arterial wall. We have recently shown that matrix metalloproteinases (MMPs) produced by human aortic medial smooth muscle cells are closely related to the pr oliferation of the cells, leading to the formation of atherosclerotic plaques, characteristic of intimal remodeling. For a better understand ing of the mechanism of atherogenesis, therefore, it is important to c larify the relationship between the production of matrix-degrading enz ymes and artery development. EXPERIMENTAL DESIGN: In vivo or in vitro synthesis of MMPs by SMC was analyzed by immunohistochemistry and immu noblotting. Elastase activity in the culture medium was also estimated . RESULTS: Production of proMMP 1, 2, and 3 was detected in cultured S MC isolated from the aortas of both neonates and fetuses; in medial SM C cultured from young individuals, production of proMMP-1 and -3 was e xtremely decreased, but was apparent in intimal SMC. Immunohistochemic al observation indicated that in the media of fetal or neonatal aorta, SMC synthesized large amounts of the three proMMPs; in aortas from ol der individuals, proMMP-2, but not proMMP-1 and -3, was detected in th e media, and relatively large amounts of proMMP-1, -2, and -3 were pro duced by SMC in the slightly thickened intima. Assay of elastase activ ity in the culture medium gave results similar to those for MMPs. CONC LUSIONS: We conclude that the production of proMMP-1 and -3 is associa ted with phenotypic modulation of SMC to a ''synthetic'' state, and th at the ability of SMC to produce MMPs plays an important role in the d evelopment and/or aging of the human aorta through remodeling of the e xtracellular matrix; furthermore elastase is also involved in these pr ocesses in the arterial wall.