Platelet-derived growth factor D-chain (PDGF-D) is the newest member of the PDGF family of mitogens and chemo-attractants; it is expressed in a wide variety of cell types, including vascular smooth muscle cells (SMCs). The molecular mechanisms regulating PDGF-D transcription are unknown. Here I investigated the effects of angiotensin II (ATIl) and IL-1 beta on the transcription of PDGF-D and changes in vascular SMCs phenotype. Primer extension analysis mapped a single transcriptional start site to the ccAG CGC motif of PDGF-D promoter. Several potential transcription factor binding sites such as SpI, Ets-1, NF-??B, IRF-1, p53, Smad4 and AP1 were located in the proximal 1168bp of the PDGF-D promoter. ATII-inducible Ets-1 and PDGF-D gene expression is mediated via H202. IL-I beta supresses PDGF-D promoter activity, mRNA and protein expression in SMCs through NF-??B p65, IRF-1 and HDAC1, which form complex in the PDGF-D promoter. This study provides the first direct link between NF-KB and the PDGF-D promoter, IRF-1 with any member of the PDGF family and a new example of HDAC mediated inhibition of gene expression. In summary, this study investigates for the first time the mechanisms mediating the transcriptional regulation of PDGF-D in vascular SMCs. This provides valuable insights into the molecular control of vascular phenotype, and opens up potential opportunities for therapeutic intervention.