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Anaphylactic shock is a severe allergic reaction involving multiple organs including the bronchial and cardiovascular system. Most anaphylactic mediators, like platelet-activating factor (PAF), histamine, and others, act through G protein – coupled receptors, which are linked to the heterotrimeric G proteins Gq /G 11 , G12/G13 , and Gi . The role of downstream signaling pathways activated by anaphylactic mediators in defi ned organs during anaphylactic reactions is largely unknown. Using genetic mouse models that allow for the conditional abrogation of G q /G 11 - and G 12 /G 13 -mediated signaling pathways by inducible Cre/loxP-mediated mutagenesis in endothelial cells (ECs), we show that Gq /G11 -mediated signaling in ECs is required for the opening of the endothelial barrier and the stimulation of nitric oxide formation by various infl ammatory mediators as well as by local anaphylaxis. The systemic effects of anaphylactic mediators like histamine and PAF, but not of bacterial lipopolysaccharide (LPS), are blunted in mice with endothelial G alpha q/G alpha 11 deficiency. Mice with endothelium-specific G alpha q /G alpha 11 deficiency, but not with G alpha 12/G alpha 13 deficiency, are protected against the fatal consequences of passive and active systemic anaphylaxis. This identifies endothelial Gq/G11 -mediated signaling as a critical mediator of fatal systemic anaphylaxis and, hence, as a potential new target to prevent or treat anaphylactic reactions.
Myogenic vasoconstriction is an autoregulatory function of small arteries. Recently, G-protein-coupled receptors have been involved in myogenic vasoconstriction, but the downstream signalling mechanisms and the in-vivo-function of this myogenic autoregulation are poorly understood. Here, we show that small arteries from mice with smooth muscle-specific loss of G12/G13 or the Rho guanine nucleotide exchange factor ARHGEF12 have lost myogenic vasoconstriction. This defect was accompanied by loss of RhoA activation, while vessels showed normal increases in intracellular [Ca2+]. In the absence of myogenic vasoconstriction, perfusion of peripheral organs was increased, systemic vascular resistance was reduced and cardiac output and left ventricular mass were increased. In addition, animals with defective myogenic vasoconstriction showed aggravated hypotension in response to endotoxin. We conclude that G12/G13- and Rho-mediated signaling plays a key role in myogenic vasoconstriction and that myogenic tone is required to maintain local and systemic vascular resistance under physiological and pathological condition.