Retinoic acid regulates arterial smooth muscle cell proliferation and phenotypic features in vivo and in vitro through an RAR alpha-dependent signaling pathway

We have recently shown that all-trans retinoic acid (tRA) modulates arteria l smooth muscle cell (SMC) morphologic features and biochemical composition in vitro. It has been proposed that different SMC phenotypes coexist in ar teries, which may be retrieved in culture: hence, a differential action of tRA on distinct SMC subsets is conceivable. We have examined the effect of tRA on SMC proliferation, migration, plasminogen activator activity, and ct -smooth muscle actin expression in 2 phenotypically different rat SMC popul ations, cultured respectively from the normal aortic media and from the int imal thickening (IT) after endothelial injury. tRA inhibited proliferation and increased migration and tissue-type plasminogen activator activity in b oth SMC populations, but decreased ct-smooth muscle actin only in SMC cultu red from the IT. The action of tRA is mediated by 2 families of nuclear rec eptors, RAR and RXR, each containing 3 isoforms, alpha, beta, and gamma. RA R and RAR-alpha agonists, but not RXR agonists, inhibited SMC proliferation in both cell populations and alpha-smooth muscle actin expression only in IT SMC. When administered intraperitoneally to balloon-injured rats, tRA an d RAR-alpha agonists reduced the intimal hyperplasia in the carotid artery. Our results show that tRA and synthetic retinoids can affect the prolifera tion, migration, and differentiation of SMC in vitro. Furthermore, retinoid s are able to reduce the IT induced by endothelial injury in vivo.