Synergistic effect of urotensin II with serotonin on vascular smooth muscle cell proliferation

Background Urotensin II (U-II), the most potent vasoconstrictor, and seroto nin (5-HT) are known to play an important role in pulmonary hypertension. H owever, little is known about the effect of U-II and its interaction with 5 -HT on vascular smooth muscle cell (VSMC) proliferation. Objective We assessed the interaction between U-II and 5-HT in inducing VSM C proliferation. Methods Growth-arrested rabbit VSMCs were incubated in serum-free medium wi th different concentrations of U-II and 5-HT. VSMC proliferation was examin ed by the increase in [H-3]thymidine incorporation into DNA and cell number . Results U-II or 5-HT induced [H-3]thymidine incorporation in a dose-depende nt manner with a maximal effect at a concentration of 50 nmol/l (161%) or 5 0 mu mol/l (205%), respectively. When added together, low concentrations of U-II (50 nmol/l) and 5-HT (1 mu mol/l) interacted synergistically in induc ing [H-3]thymidine incorporation (382%). These effects on [H-3]thymidine in corporation were paralleled by an increase in cell number. The G-protein in activator GDP-beta -S (100 mu mol/l), protein kinase C (PKC) inhibitor Ro31 -8220 (0.1 mu mol/l), Src family tyrosine kinase inhibitor PP2 (1 mu mol/l) , and mitogen-activated protein kinase (MAPK) kinase inhibitor PD098059 (10 mu mol/l) inhibited the mitogenic effects of U-II and 5-HT and also their interaction in inducing [H-3]thymidine incorporation. Conclusion Our results suggest that U-II and 5-HT may induce the synergisti c interaction in inducing VSMC proliferation via a G-protein-coupled recept or/PKC/Src tyrosine kinase/MAPK pathway, thus contributing to the relativel y rapid development of atherosclerosis in hypertensive vascular disease. J Hypertens 19:2191-2196 (C) 2001 Lippincott Williams & Wilkins.