RETINOID RECEPTOR EXPRESSION AND ALL-TRANS-RETINOIC ACID-MEDIATED GROWTH-INHIBITION IN VASCULAR SMOOTH-MUSCLE CELLS

Background Retinoids have been used in the successful treatment of a v ariety of human hyperproliferative diseases. Their role in smooth musc le cell (SMC) growth control, however, has not been clearly establishe d. The present study was designed to assess the retinoid receptor mRNA expression profile in SMCs and to determine whether retinoids exert a growth-inhibitory effect in these cells. Methods and Results Five of the six retinoid receptors were expressed in both cultured SMCs and ao rta as determined by Northern blotting or reverse transcription-polyme rase chain reaction. Receptor activity was demonstrated in SMCs with t he use of a reporter assay with a retinoid receptor DNA binding sequen ce linked to a chloramphenicol acetyltransferase reporter gene. DNA sy nthesis and cell proliferation assays were performed to show that all- trans retinoic acid (atRA) antagonized platelet-derived growth factor- BB and serum-stimulated SMC growth. Growth inhibition was distal to ea rly growth-signaling events because induction of c-fos, c-jun, and egr -1 mRNA was unaffected by atRA. However, with an activated protein-1-l inked chloramphenicol acetyltransferase reporter; atRA was shown to in hibit the activity of activated protein-1-dependent transcription in a transient transfection assay. Conclusions These results establish the presence of functional retinoid receptors in SMCs and document the gr owth-inhibitory action of atRA on these cells. Retinoid compounds, alr eady in clinical use as antiproliferative agents for nonvascular indic ations, should be assessed further in in vivo models of intimal diseas e.