INDUCIBLE PDGF A-CHAIN TRANSCRIPTION IN SMOOTH-MUSCLE CELLS IS MEDIATED BY EGR-1 DISPLACEMENT OF SP1 AND SP3

Platelet-derived growth factor (PDGF) A-chain is expressed by vascular smooth muscle cells (SMC) in a variety of pathological settings. Phor bol 12-myristate 13-acetate (PMA) increases A-chain transcription and was used as a model agonist. Transient transfection analysis identifie d a region in the promoter that is required for inducibility, located between base pairs -71 and -55 from the transcription start site. This region contains overlapping recognition elements for members of the S p and Egr families. Egr-1 transcript and protein increased after PMA t reatment, whereas Sp1 and Sp3 levels remain unchanged. Egr-1 expressio n and PDGF A-chain promoter activity also increased in cells exposed t o PDGF or mechanical injury. In vitro binding assays demonstrated that Egr-1, Sp1, and Sp3 can bind to this promoter region and that increas ing Egr-1 can displace both Sp1 and Sp3. In an in vivo model of arteri al injury, Egr-1 expression was induced concurrently with the expressi on of PDGF-A in SMC. Displacement of Sp1 and Sp3 by Egr-1 is correlate d with inducible PDGF A-chain expression in the vessel wall.