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Purpose: Smooth muscle cell (SMC) migration is a critical element in the development of intimal hyperplasia. The effect of endothelial cells (ECs) on SMC migration and the modulation of this cell-to-cell interaction by extracellular matrix is not well understood. Methods: To examine this relationship SMCs and ECs were cocultured on opposite sides of a semipermeable membrane and were compared with SMCs cultured alone. To assess migration SMCs were plated at confluent density into the center of the membrane with a steel fence. After the fence was removed, SMCs were treated for 2 hours with mitomycin C (20 @mg/ml) to assess migration independent of proliferation. Cell migration was measured with morphometry. Experiments were performed on plastic and membranes coated with fibronectin or type I collagen (n >= 8/group). Cell adhesiveness was quantitated by cell attachment and spreading assays. Results: ECs stimulated SMC migration by 187% when compared with SMCs cultured alone on plastic and by 160% when cultured on fibronectin ( p < 0.01). Type I collagen stimulated migration of SMCs cultured alone and prevented EC stimulated migration in cocultured SMCs ( p < 0.01). Cell adhesiveness was significantly increased in cocultured SMCs compared with SMCs cultured alone regardless of whether cells were cultured on plastic (EC/SMC, 13.5 + 0.6 SMCs/high power field vs SMC, 8.9 + 0.5, p < 0.01), fibronectin (16.3 + 0.8 vs 12.3 + 0.7, p < 0.01) or type I collagen (15.5 + 1.0 vs 12.4 + 0.6, p < 0.01). ECs increased SMC cell spreading on plastic and fibronectin when compared with SMCs cultured alone. No difference in SMC cell spreading was seen in the presence or absence of ECs when cells were cultured on type I collagen. EC-SMC contact was not required; EC-conditioned media alone increased SMC migration by 75% when compared with SMCs cultured alone. Our data suggest that ECs increase SMC migration by a diffusable molecule that may also alter SMC adhesion molecule expression. Extracellular matrix composition can attenuate these effects. (J Vasc Surg 1996;24:51-7.)