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The tone of vascular smooth muscle cells is a primary determinant of the total peripheral vascular resistance and hence the arterial blood pressure. Most forms of hypertension ultimately result from an increased vascular tone that leads to an elevated total peripheral resistance^,,. Regulation of vascular resistance under normotensive and hypertensive conditions involves multiple mediators, many of which act through G protein–coupled receptors on vascular smooth muscle cells. Receptors that mediate vasoconstriction couple with the G-proteins G_q-G₁₁ and G₁₂-G₁₃ to stimulate phosphorylation of myosin light chain (MLC) via the Ca²⁺/MLC kinase– and Rho/Rho kinase–mediated signaling pathways, respectively^,,. Using genetically altered mouse models that allow for the acute abrogation of both signaling pathways by inducible Cre/loxP-mediated mutagenesis in smooth muscle cells, we show that G_q-G₁₁ …