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To isolate the genes involved in the cell cycle G1 phase progression of arterial smooth muscle cells (SMCs), a cDNA clone (M11) was previously selected by differential hybridization screening of a mid-G1 serum-stimulated SMC cDNA library. The delay of induction after mitogenic stimulation, time of expression, and need for new protein synthesis for full expression made it possible to classify this gene in the "delayed early" gene group. Determination of the partial M11 cDNA sequence showed full homology with the osteopontin gene (secreted phosphoprotein 1, 2ar), an Arg-Gly-Asp-containing extracellular matrix protein. Osteopontin mRNA was also detected in the aorta at levels as high as in the kidney but lower than in bone, two tissues in which it has been previously detected. In vitro analysis of osteopontin expression in serum-stimulated quiescent SMCs and asynchronously cycling SMCs demonstrated that osteopontin overexpression was associated with SMC proliferation. In view of our results, the high osteopontin expression observed by others in the injured carotid artery could be explained by the involvement of SMCs in the proliferative process. Taken together, these results suggest that osteopontin may play an important role in pathological processes that are associated with arterial SMC proliferation, such as atherosclerosis or restenosis.