all- Trans -Retinoic Acid Reduces Neointimal Formation and Promotes Favorable Geometric Remodeling of the Rat Carotid Artery After Balloon Withdrawal Injury

Abstract

Background-The multifactorial and unpredictable nature of human restenosis will probably necessitate interventional strategies that target multiple processes involved in acute vascular narrowing. Retinoids (eg, all-trans-retinoic acid, atRA) represent a growing class of pleiotropic biological response modifiers with demonstrable efficacy in managing several pathological conditions. In this report, we have initiated studies to examine the hypothesis that atRA limits neointimal formation after experimental vascular injury. Methods and Results-Rats were predosed with atRA (30 mg ⅐ kg Ϫ1 ⅐ d Ϫ1 PO) or corn oil 4 days before balloon withdrawal injury (BWI) of the left common carotid artery and continued on this drug regimen for an additional 14 days. High-performance liquid chromatographic analysis documented therapeutic levels of atRA in serum and vascular tissue. atRA depressed peak DNA synthesis in the tunica media of BWI vessels (PϽ0.05). Histomorphometry revealed atRA-mediated reductions in neointimal area, neointimal cell number, and intimal/medial area ratio as well as significant increases in vessel wall perimeter (PϽ0.05). Such changes in vascular architecture contributed to a 35% to 37% increase in the luminal area of BWI vessels exposed to atRA (PϽ0.005 compared with controls). Conclusions-atRA reduces neointimal mass and elicits favorable geometric remodeling of the injured rat carotid artery.

Retinoids and Pulmonary Hypertension

“…3,4 In the rat carotid injury model, ATRA decreased neointimal cellularity and extracellular matrix deposition, leading to increased lumen diameter and area. [5][6][7] ATRA also induced favorable remodeling of the injured artery in rabbits. 8 In cultured aortic smooth muscle cells, ATRA induced apoptosis 9 and inhibited proliferation induced by serotonin, 10 platelet-derived growth factor, 11 endothelin-1, 12 and angiotensin II.…”

Regulation and characteristics of vascular smooth muscle cell phenotypic diversity

“…37 Interestingly, in adult SMCs, RA can promote either the synthetic or the contractile SMC phenotype, though its contractile phenotype promoting effects are dominant. 38 For example, expression of contractile SMC markers including smoothelin and SM-MHC is increased upon RA treatment, 6 and most studies indicate that retinoids decrease SMC proliferation. 39 In addition, RA lowers SMC migration through induction of specific ECM proteins.…”

The early- and late stages in phenotypic modulation of vascular smooth muscle cells: Differential roles for lysophosphatidic acid

“…Studies with cultured cells [12][13][14][15][16][17] and with intact cultured vessels [18][19][20][21] have shown that mechanical stimulation is able to maintain VSMC in the differentiated phenotype, typified by a high level of SMC-specific marker genes or a low proliferation rate. Soluble biochemical factors, including platelet-derived growth factor (PDGF) [22][23][24][25], transforming growth factor (TGF)-β [26,27], and retinoic acid [28][29][30][31] have been shown to affect PM. Extracellular matrix molecules, such as heparin, fibrillar collagen type I, collagen type IV, and laminin have also been shown to have significant effects on PM [32][33][34][35][36][37][38][39].…”