title: Mas receptor is involved in the estrogen-receptor induced nitric oxide-dependent vasorelaxation.
abstract: The Mas receptor is involved in the angiotensin (Ang)-(1-7) vasodilatory actions by increasing nitric oxide production (NO). We have previously demonstrated an increased production of Ang-(1-7) in human umbilical vein endothelial cells (HUVEC) exposed to estradiol (E2), suggesting a potential cross-talk between E2 and the Ang-(1-7)/Mas receptor axis. Here, we explored whether the vasoactive response and NO-related signalling exerted by E2 are influenced by Mas. HUVEC were exposed to 10nM E2 for 24h in the presence or absence of the selective Mas receptor antagonist A779, and the estrogen receptor (ER) antagonist ICI182780 (ICI). E2 increased Akt and endothelial nitric oxide synthase (eNOS) mRNA and protein expression, measured by RT-PCR and Western blot, respectively. Furthermore, E2 increased Akt activity (determined by the levels of phospho-Ser473) and eNOS activity (by the enhanced phosphorylation of Ser1177, the activated form), resulting in increased NO production, which was measured by the fluorescence probe DAF-2-FM. These signalling events were dependent on ER and Mas receptor activation, since they were abolished in the presence of ICI or A779. In ex-vivo functional experiments performed with a small-vessel myograph in isolated mesenteric vessels from wild-type mice pre-contracted with noradrenaline, the relaxant response to physiological concentrations of E2 was blocked by ICI and A779, to the same extent to that obtained in the vessels isolated from Mas-deficient. In conclusion, E2 induces NO production and vasodilation through mechanisms that require Mas receptor activation.
authors.affiliation: INCLIVA Biomedical Research Institute, Hospital Clínico de Valencia, and Department of Physiology, University of Valencia, Spain.
authors.forename: Agua
authors.initials: A
authors.lastname: Sobrino
authors.affiliation: Department of Pharmacology, University Autonoma of Madrid, Spain.
authors.forename: Susana
authors.initials: S
authors.lastname: Vallejo
authors.affiliation: INCLIVA Biomedical Research Institute, Hospital Clínico de Valencia, and Department of Physiology, University of Valencia, Spain.
authors.forename: Susana
authors.initials: S
authors.lastname: Novella
authors.affiliation: INCLIVA Biomedical Research Institute, Hospital Clínico de Valencia, and Department of Physiology, University of Valencia, Spain.
authors.forename: Macarena
authors.initials: M
authors.lastname: Lázaro-Franco
authors.affiliation: INCLIVA Biomedical Research Institute, Hospital Clínico de Valencia, and Department of Physiology, University of Valencia, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Mompeón
authors.affiliation: INCLIVA Biomedical Research Institute, Hospital Clínico de Valencia, and Department of Physiology, University of Valencia, Spain.
authors.forename: Carlos
authors.initials: C
authors.lastname: Bueno-Betí
authors.affiliation: Department of Pharmacology and Therapeutics, School of Medicine & School of Pharmacy, University College Cork, Cork, Ireland.
authors.forename: Thomas
authors.initials: T
authors.lastname: Walther
authors.affiliation: Department of Pharmacology, University Autonoma of Madrid, Spain.
authors.forename: Carlos
authors.initials: C
authors.lastname: Sánchez-Ferrer
authors.affiliation: Department of Pharmacology, University Autonoma of Madrid, Spain.
authors.forename: Concepción
authors.initials: C
authors.lastname: Peiró
authors.affiliation: INCLIVA Biomedical Research Institute, Hospital Clínico de Valencia, and Department of Physiology, University of Valencia, Spain. Electronic address: carlos.hermenegildo@uv.es.
authors.forename: Carlos
authors.initials: C
authors.lastname: Hermenegildo
mesh_terms: D000818:Animals; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009569:Nitric Oxide / Q000502:physiology*; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D011960:Receptors, Estrogen / Q000502:physiology*; D043562:Receptors, G-Protein-Coupled / Q000502:physiology*; D014664:Vasodilation / Q000502:physiology*
chemical_list: D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D011960:Receptors, Estrogen; D043562:Receptors, G-Protein-Coupled; D009569:Nitric Oxide
keywords: Endothelial cells; Estradiol; Estrogen receptor; Mas receptor; Nitric oxide