Inagami T. Molecular structure and transcriptional regulation of the gene for the platelet-derived growth factor alpha receptor in cultured vascular smooth muscle cells

PDGF has been shown to contribute to hypertrophy in vas-cular smooth muscle cells (VSMC). PDGF-AA differentially promotes protein synthesis in VSMC from spontaneously hypertensive rats (SHR) but not in those from Wistar-Kyoto rats (WKY). This observation has led us to postulate a role for PDGF a receptor (PDGFR-a) in the hypertensive hypertrophy of blood vessels. Western and Northern blot analyses demonstrated a high and specific expression of the PDGFR-a protein and mRNA in SHR cells but not in WKY cells. To clarify the mechanism of the differential expression of the PDGFR-cv gene, we isolated the promoter region of the gene. Studies on the promoter functions indicated that this promoter is active in SHR cells but not in WKY cells. The regulatory domain responsible for this difference was narrowed to the sequence between-246 and-139, which enhanced the promoter activity of SHR fivefold over the basal activity. DNase I footprinting and gel-shift assay indi-cated that this sequence specifically interact with nuclear proteins from VSMC through the binding site for CCAAT/ enhancer-binding proteins, and members of the C/en-hancer-binding protein family play a significant role in the strain-specific transcription of the PDGFR-a gene. (J. Clin. Invest. 1995.96:558-567.) Key words: vascular smooth mus-cle cells * vascular hypertrophy * platelet-derived growth factor c-receptor * promoter activity * CCAAT/enhancer-binding protein