Activation of PI3K/Akt pathway mediated by estrogen receptors accounts for estrone-induced vascular activation of cGMP signaling.

Estrone (E1) produces remarkable vascular effects, including relaxation, modulation of proliferation, apoptosis and cell adhesion. This study investigated the role of estrogen receptors and endothelial signaling pathways in the vascular relaxation promoted by E1. Aortic rings from male Wistar rats (250-300 g) were contracted with phenylephrine and stimulated with graded concentrations of E1. The concentration-dependent relaxation induced by E1 was abolished after removal of the endothelium or incubation with the estrogen receptor antagonist ICI 182,780. G protein-coupled estrogen receptor antagonism did not alter the E1 effect. Pretreatment of endothelium-intact arteries with inhibitors of nitric oxide synthase, guanylyl cyclase, calmodulin (CaM) and PI3K reduced the E1-induced vasorelaxation. Incubation with inhibitors of the MEK/ERK1/2 or p38MAPK pathways did not alter the E1 vasorelaxation. Similarly, inhibition of cyclooxygenase or blockade of potassium channels did not change the E1 effect. Western blot analysis evidenced that E1 induces phosphorylation of eNOS, PI3K and Akt in rat aorta. Our data demonstrate that E1 induces aortic vascular relaxation through classic estrogen receptors activation on the endothelium. We also identify CaM and PI3K/Akt pathways as critical mediators of the NO-cGMP signaling activation by E1. These findings contribute to the notion that this estrogen regulates arterial function and represents another link, besides 17β-estradiol (E2), between postmenopause and vascular dysfunction.