Key result
Rho kinase inhibitors block agonist-induced RhoA activation and sustained vascular smooth muscle contraction.
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Ca2+ sensitization of vascular smooth muscle (VSM) contraction involves Rho-dependent and Rho-kinase-dependent suppression of myosin phosphatase activity. We previously demonstrated that excitatory agonists in fact induce activation of RhoA in VSM. In this study, we demonstrate a novel Ca2+-dependent mechanism for activating RhoA in rabbit aortic VSM. High KCl-induced membrane depolarization as well as noradrenalin stimulation induced similar extents of sustained contraction in rabbit VSM. Both stimuli also induced similar extents of time-dependent, sustained increases in the amount of an active GTP-bound form of RhoA. Consistent with this, the Rho kinase inhibitors HA1077 and Y27632 inhibited both contraction and the 20-kDa myosin light chain phosphorylation induced by KCl as well as noradrenalin, with similar dose-response relations. Either removal of extracellular Ca2+ or the addition of a dihydropyridine Ca2+ channel antagonist totally abolished KCl-induced Rho stimulation and contraction. The calmodulin inhibitor W7 suppressed KCl-induced Rho activation and contraction. Ionomycin mimicked W7-sensitive Rho activation. The expression of dominant-negative N19RhoA suppressed Ca2+-induced Thr695 phosphorylation of the 110-kDa regulatory subunit of myosin phosphatase and phosphorylation of myosin light chain in VSM cells. Finally, either the combination of extracellular Ca2+ removal and depletion of the intracellular Ca2+ store or the addition of W7 greatly reduced noradrenalin-induced and the thromboxane A2 analogue-induced Rho stimulation and contraction. Taken together, these results indicate the existence of the thus-far unrecognized Ca2+-dependent Rho stimulation mechanism in VSM. Excitatory receptor agonists are suggested to use this pathway for simulating Rho.
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Sakurada et al. (2003) studied Vascular smooth muscle contraction. High KCl-induced membrane depolarization, noradrenalin, and Rho kinase inhibitors (HA1077, Y27632) vs. Extracellular Ca2+ removal, dihydropyridine Ca2+ channel antagonist, or calmodulin inhibitor W7 was evaluated on Sustained vascular smooth muscle contraction, active GTP-bound RhoA levels, and 20-kDa myosin light chain phosphorylation. High KCl and noradrenalin induced Ca2+-dependent increases in active GTP-bound RhoA and sustained contraction in rabbit aortic VSM, which were inhibited by Rho kinase inhibitors HA1077 and Y27632.
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