VASCULAR SMOOTH MUSCLE CELLS IN DEVELOPMENT AND PROGRESSION OF VASCULAR DISEASE

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The development and progression of several vascular diseases depend on the migration and proliferation of vascular smooth muscle cells (VSMC) and their interaction with extracellular matrix (ECM). We have found previously that this interaction is due in part to the invasion of reconstituted basement membrane (Matrigel) by VSMC in response to PDGF. Proliferative (dedifferentiated) VSMC exhibit fivefold greater invasiveness as compared with post-confluent (differentiated) VSMC. We have demonstrated that intracellular calcium dynamics play an important role in VSMC invasion but not in chemotaxis. Chemotaxis reflects the ability of cells to attach to a substrate and migrate in response to a chemoattractant. Chemoinvasion requires the additional ability of cells to degrade a barrier. We have demonstrated 72 KD type IV and 92 KD type IV collagenase activity by zymography in invasive VSMC. Northern blot analyses have indicated mRNA for 72 KD type IV collagenase but not 92 KD type IV collagenase in these cells. Invasive VSMC also express mRNA for the tissue inhibitors of matrix metalloproteinases (TIMPs) - reflecting the importance of a balance between positive and negative regulators. Chemoinvasion assays employing antiserum to the 72 KD type IV collagenase, nonimmune serum, and antiserum to the 92 KD type IV collagenase, have demonstrated that VSMC invasion in response to PDGF is mediated by the 72 KD type IV collagenase. Chemotaxis is less dependent on the 72 KD type IV collagenase. Because these collagenases are secreted in zymogen form, activation is required for degradation of ECM. Experimental results employing BAPTA (a chelator of intracellular calcium) and ionomycin (a calcium ionophore) suggest calcium may be important in this activation.