Retinoids: versatile biological response modifiers of vascular smooth muscle phenotype.

Proper regulation of vascular smooth muscle cell (SMC) differentiation and growth is critical for vasculogenesis and the maintenance of homeostasis in the mature vessel wall.1,2 Perturbations in the molecular circuitry governing SMC differentiation and growth are thought to be of central importance in the pathogenesis of atherosclerosis, hypertension, and restenosis after procedural revascularizations. The identification of membrane-bound receptors and the delineation of their respective signaling pathways have yielded insight into the mechanisms that control SMC differentiation and growth3 and have provided molecular targets for therapy of vascular disease.4 In recent years, several nuclear receptor binding factors have been shown to regulate SMC differentiation and growth. The steroid receptor superfamily5 has been of particular interest in this regard. Steroid receptors are ligand-activated transcription factors that bind discrete cis elements within the regulatory regions of a growing list of target genes. This family of nuclear receptors includes the estrogen receptors,6 the vitamin D receptor,7 the peroxisome proliferator-activated receptors,8 and the retinoid receptors.9 Retinoids and the receptors they bind are gaining an increasingly important role in both cardiovascular development and the response of blood vessels to injury. In this review, we will focus specifically on the emerging role of retinoids as critical regulators of vascular SMC differentiation and growth. We first provide a brief history of retinoid biology as well as its intracellular fates with particular emphasis on the retinoid receptors. We then summarize the literature to date supporting retinoids as regulators of vasculogenesis and SMC differentiation. An update on the role of retinoids in the control of SMC growth is then considered followed by a summary of the recent corroborative papers showing an inhibition of neointimal formation with retinoid administration. We conclude the review with future studies that should be pursued to gain mechanistic insight into how these pleiotropic biological response modifiers regulate vascular SMC phenotype.