Abstract
To investigate the effects of the balance in activity of RhoA and Rac1 on the shock-induced biphasic change in vascular reactivity and the related mechanism. Vascular reactivity after hemorrhagic shock shows a biphasic change. RhoA and Rac1 are the main members of a family of Rho GTPases; whether and how they participate in the regulation of the biphasic change in vascular reactivity after shock is not known. The relationship of the balance of the activity RhoA and Rac1 with the changes in vascular reactivity after hemorrhagic shock, the effects of artificially changing the balance of RhoA and Rac1 activity on vascular reactivity, and the roles of Rho kinase and p21-activated kinase (PAK) in RhoA/Rac1 regulation of vascular reactivity were observed in isolated superior mesenteric arteries (SMAs) from hemorrhagic shocked rats and hypoxia-treated vascular smooth muscle cells (VSMCs). The reactivity of SMAs and VSMCs to norepinephrine after shock or hypoxia was positively correlated with changes in the RhoA and Rac1 activity ratio. Artificially changing the balance in activity of RhoA and Rac1 significantly changed the shock-induced biphasic response of vascular reactivity. Specific antagonist of Rho kinase and PAK (Y-27632 and PAK-18) respectively abolished the effect of activation of RhoA and Rac1. Activation of RhoA significantly increased the activity of Rho kinase and inhibited the activity of Rac1 in SMAs. Rac1 activation significantly increased the activity of PAK and decreased the activity of RhoA. The balance in the activity of RhoA and Rac1 participated in the biphasic vascular reactivity seen after hemorrhagic shock. RhoA and Rac1 regulation of the vascular reactivity after shock are closely related to Rho kinase and the PAK pathway. RhoA regulates vascular reactivity mainly through activation of Rho kinase and inhibition of Rac1. Rac1 regulates vascular reactivity mainly through inhibition of RhoA and activation of PAK. These findings have potential significance for the treatment of vascular hyporesponsiveness.
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