ROLE OF VASCULAR SMOOTH MUSCLE CELLS IN VASCULAR DISEASE

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The migration, proliferation, and neointimal accumulation of vascular smoot muscle cells (VSMCs) are key events in the development and progression of many vascular diseases and a predictable consequence of mechanical injury t the blood vessel. VSMCs in vivo are surrounded by and embedded in extracellular matrices (ECMs) that must be traversed during migration. In many other cell types, migration across ECM barriers involves the local destruction or degradation of these barriers by extracellular proteases. Principle among such proteases are those belonging to the matrix metalloproteinase (MMP) family. Using an in vitro assay to monitor and manipulate the ability of VSMCs to degrade a defined ECM barrier as they migrate toward a chemo-attractant, we demonstrate that VSMCs isolated from the rat thoracic aorta and maintained in a proliferating or "synthetic" state readily migrate through an ECM barrier of reconstituted basement membrane. The migration of growth arrested/ differentiated VSMCs toward th chemoattractant both in the presence and in the absence of the barrier is less than 20% (p<0.001) that of proliferating cells. A peptide that mimics the inhibitory propeptide region of all MMPs and antisera caple of neutralizing the activity of the 72 kD Type IV collagenase (MMP-2) blocked migration of proliferating cells through the barrier by more than 80% (p<0.005), but did not significantly affect migration that occurred in the absence of the barrier. Northern blotting and zymogramic analyses indicate that MMP2 is the principal MMP expressed and secreted by these cells. MMP2 activity expressed by serum starved/differentiated VSMCs as measured by a fluorescent peptide cleavage assay was less than 5% of that measured in proliferating VSMCs. Membrane-type MMP (MT-MMP), a recently described integral plasma membrane protein that activates MMP-2, is differentially expressed in VSMCs. Specifically, proliferating (migratory) VSMCs express 2 3 fold more MT-MMP mRNA than differentiated/growth arrested cells. In contrast, MMP-2 mRNA appears to be equally expressed. These results demonstrate that VSMCs migrate through an ECM barrier similar in compositio to one that normally surrounds them and that this ability is regulated by the phenotypic state of the cell and that MT-MMP may be an important regulator of the MMP-2 proteolytic cascade in VSMC.