Retinoic acid regulates arterial smooth muscle cell proliferation and phenotypic features in vivo and in vitro through an RARalpha-dependent signaling pathway.
We have recently shown that all-trans retinoic acid (tRA) modulates arterial smooth muscle cell (SMC) morphologic features and biochemical composition in vitro. It has been proposed that different SMC phenotypes coexist in arteries, 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 alpha-smooth muscle actin expression in 2 phenotypically different rat SMC populations, cultured respectively from the normal aortic media and from the intimal thickening (IT) after endothelial injury. tRA inhibited proliferation and increased migration and tissue-type plasminogen activator activity in both SMC populations, but decreased alpha-smooth muscle actin only in SMC cultured from the IT. The action of tRA is mediated by 2 families of nuclear receptors, RAR and RXR, each containing 3 isoforms, alpha, beta, and gamma. RAR 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 and RAR-alpha agonists reduced the intimal hyperplasia in the carotid artery. Our results show that tRA and synthetic retinoids can affect the proliferation, migration, and differentiation of SMC in vitro. Furthermore, retinoids are able to reduce the IT induced by endothelial injury in vivo.
Neuville
P
P
Department of Pathology, University of Geneva-CMU, Switzerland.
Yan
Z
Z
Gidlöf
A
A
Pepper
M S
MS
Hansson
G K
GK
Gabbiani
G
G
Sirsjö
A
A
D000818:Animals; D002339:Carotid Arteries / Q000187:drug effects / Q000473:pathology; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D008297:Male; D008666:Metalloendopeptidases / Q000502:physiology; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000473:pathology; D010641:Phenotype; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D018168:Receptors, Retinoic Acid / Q000502:physiology*; D000072482:Retinoic Acid Receptor alpha; D014212:Tretinoin / Q000494:pharmacology*
C000607073:Rara protein, rat; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D014212:Tretinoin; D008666:Metalloendopeptidases