The modulation of vascular smooth muscle cells (VSMCs) from the quiescent phenotype to the proliferative and migratory phenotype is a critical event in the pathogenesis of atherosclerosis. To-date several growth factors, including platelet-derived growth factor, PDGF, have been shown to induce VSMC proliferation and migration. To further understand the mechanism of PDGF-induced VSMC activation, quiescent human coronary artery SMC were treated with PDGF, and the genes that displayed transcriptional changes within 3 and 8 h were identified using differential display RT-PCR, real-time PCR, nucleotide sequencing and bioinformatics. Eleven genes that were highly upregulated or down-regulated at 3 and/or 8 h by PDGF, designated growth-factor regulated VSMC genes (GRSG1-11), were analyzed. GRSG5 and GRSG9-1 were identified as cortactin and cytochrome c oxidase subunit II, respectively. The remaining nine GRSGs were novel. GRSG3, 4, 5 and 9-2 showed wide tissue distribution whereas GRSG10-1, 10-2, and 11 were tissue specific. Cortactin was localized by immunohistochemical staining to the neointima and fibrous cap of human coronary artery atherosclerotic plaques. Domain analysis of open reading frames suggest that the novel GRSGs may participate in signaling, metabolic, translational or migrational processes during PDGF-induced VSMC activation.