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Urotensin II induces phenotypic differentiation, migration, and collagen synthesis of adventitial fibroblasts from rat aorta

Background Urotensin II is a new potent vasoconstrictor. Nevertheless, little is known about its effects on the activation of adventitial fibroblasts. Objective To explore the effects of urotensin II on phenotypic differentiation, migration, and collagen I synthesis of rat aortic adventitial fibroblasts. Methods Growth-arrested adventitial fibroblasts were incubated in serum-free medium with urotensin II and some inhibitors of signal transduction pathways. The α-smooth muscle-actin expression, collagen I synthesis and migration of adventitial fibroblasts induced by urotensin II were evaluated by western blot, enzyme-linked immunosorbant assay, and the transwell technique, respectively. Results Urotensin II induced the α-smooth muscle-actin expression in a dose-dependent and time-dependent manner, with maximal effect at a concentration of 10−8 mol/l at 24 h (79.9%); it also caused a dose-dependent increase in collagen I synthesis, with maximal effect at a concentration of 10−7 mol/l (42.6%). The Ca2+ channel blocker nicardipine (10−5 mol/l), protein kinase C inhibitor H7 (10−5 mol/l), Rho protein kinase inhibitor Y-27632 (10−5 mol/l), calcineurin inhibitor cyclosporine A (10−5 mol/l), and mitogen-activated protein kinase inhibitor PD98059 (10−5 mol/l) inhibited urotensin II-induced increases in α-smooth muscle-actin expression and collagen synthesis. Meanwhile, urotensin II stimulated the migration of adventitial fibroblasts dose dependently, with maximal effect at a concentration of 10−8 mol/l, which was 5.7-fold greater than that of the control. This effect could also be inhibited by PD98059, H7, cyclosporine A, and Y-27632 but not nicardipine. Conclusion Urotensin II may stimulate adventitial fibroblasts phenotypic conversion, migration, and collagen I synthesis through the protein kinase C, mitogen-activated protein kinase, calcineurin, Rho kinase, and/or Ca2+ signal transduction pathways, contributing to the development of vascular remodeling through adventitial fibroblasts activation.