Laminin and elastin, two major constituents of the extracellular matrix, bind to cells via the elastin-laminin receptor (ELR), a receptor distinct from integrins. Despite the ubiquitous nature of elastin and laminin in the matrix, the consequences of activation of the ELR are unknown. Because integrins are capable of mechanosensitive transduction, we hypothesized that the ELR would exert a similar function. Accordingly, we examined the effects of cyclical stretch on canine coronary smooth muscle gene expression and proliferation that are mediated by the ELR. Northern blot analyses showed a 31% decrease in serum-induced expression of c-fos when cells were stretched for 30 min on elastin, but no change in expression was observed on collagen. Serum-induced proliferation of stretched cells was markedly attenuated on elastin when compared with collagen. Both the molecular (decreased c-fos expression) and biological (decreased proliferation) responses on elastin were restored after blockade of the ELR with the elastin fragment hexapeptide (valine-glycine-valine-alanine-proline-glycine, VGVAPG). The inhibition was specific for this peptide, as another hydrophobic hexapeptide (valine-serine-leucine-serine-proline-glycine, VSLSPG) did not inhibit the responses. These results demonstrate that cyclic stretch inhibits c-fos expression and proliferation of coronary vascular smooth muscle cells grown on elastin matrixes, a mechanosensitive response that is transduced by the ELR.