© 1999 American Heart Association, Inc.
Vascular Biology |
Retinoic Acid Regulates Arterial Smooth Muscle Cell Proliferation and Phenotypic Features In Vivo and In Vitro Through an RAR
-Dependent Signaling Pathway
From the Departments of Pathology (P.N., G.G.) and Department of Morphology (M.S.P.), University of Geneva-CMU, Switzerland; and Center for Molecular Medicine (Z.-q Y., A.G., G.K.H., A.S.), Karolinska Hospital, Karolinska Institute, Stockholm, Sweden.
Correspondence to Prof Giulio Gabbiani, University of Geneva-CMU, Department of Pathology, 1 rue Michel-Servet, 1211 Geneva 4, Switzerland. E-mail giulio.gabbiani{at}medecine.unige.ch
Abstract—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
-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 -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, , ß,
and 
. RAR and RAR- agonists, but not RXR agonists, inhibited SMC
proliferation in both cell populations and -smooth muscle actin
expression only in IT SMC. When administered
intraperitoneally to balloon-injured rats, tRA and
RAR- 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.
Key Words: smooth muscle cell heterogeneity • smooth muscle cell motility • smooth muscle cell differentiation • intimal thickening
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