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The action of oestrogen has traditionally been attributed to the activation of nuclear receptors (ERα and ERβ). A third receptor, the G protein-coupled oestrogen receptor (GPER), has been described as mediator of the rapid action of oestrogen. Based on the possible protective role of oestrogen in the cardiovascular system, the present study was designed to determine whether selective GPER activation induces relaxation of mesenteric resistance arteries in both sexes and which signalling pathways are involved.Third-order mesenteric arteries were isolated, and concentration-response curves were plotted following the cumulative addition of the selective GPER agonist G-1 (1 nM − 10 μM) following induction of contraction with phenylephrine (3 μM). The vasodilatory effects of G-1 were assessed before and after removal of the endothelium or incubation for 30 min with nitric oxide synthase (Nω-nitro-L-arginine methyl ester - L-NAME, 300 μM) and cyclooxygenase (indomethacin – INDO, 10 μM) inhibitors alone or combined, PI3K-Akt pathway inhibitor (LY-294,002, 2.5 μM) or a potassium channel blocker (tetraethylammonium – TEA, 5 mM). GPER immunolocalisation was also performed on the investigated arteries.The tested GPER agonist induced concentration-dependent relaxation of the mesenteric resistance arteries without differences related to sex that were partially endothelium dependent, mainly mediated by the PI3K-Akt-eNOS pathway and attenuated by nonspecific potassium channel blockade. In addition, the endothelial GPER immunolocalisation was stronger among females.This evidence provides a new perspective for understanding the mechanisms involved in the vascular responses triggered by oestrogen via GPER in both sexes.