title: Activation of G protein-coupled estrogen receptor induces endothelium-independent relaxation of coronary artery smooth muscle.
abstract: Estrogens can either relax or contract arteries via rapid, nongenomic mechanisms involving classic estrogen receptors (ER). In addition to ERα and ERβ, estrogen may also stimulate G protein-coupled estrogen receptor 1 (GPER) in nonvascular tissue; however, a potential role for GPER in coronary arteries is unclear. The purpose of this study was to determine how GPER activity influenced coronary artery reactivity. In vitro isometric force recordings were performed on endothelium-denuded porcine arteries. These studies were augmented by RT-PCR and single-cell patch-clamp experiments. RT-PCR and immunoblot studies confirmed expression of GPER mRNA and protein, respectively, in smooth muscle from either porcine or human coronary arteries. G-1, a selective GPER agonist, produced a concentration-dependent relaxation of endothelium-denuded porcine coronary arteries in vitro. This response was attenuated by G15, a GPER-selective antagonist, or by inhibiting large-conductance calcium-activated potassium (BK(Ca)) channels with iberiotoxin, but not by inhibiting NO signaling. Last, single-channel patch-clamp studies demonstrated that G-1 stimulates BK(Ca) channel activity in intact smooth muscle cells from either porcine or human coronary arteries but had no effect on channels isolated in excised membrane patches. In summary, GPER activation relaxes coronary artery smooth muscle by increasing potassium efflux via BK(Ca) channels and requires an intact cellular signaling mechanism. This novel action of estrogen-like compounds may help clarify some of the controversy surrounding the vascular effects of estrogens.
authors.affiliation: Michael E. DeBakey Institute-Division of Women's Health, Texas A & M University, College Station, Texas, 77843, USA.
authors.forename: Xuan
authors.initials: X
authors.lastname: Yu
authors.forename: Handong
authors.initials: H
authors.lastname: Ma
authors.forename: Scott A
authors.initials: SA
authors.lastname: Barman
authors.forename: Alexander T
authors.initials: AT
authors.lastname: Liu
authors.forename: Minga
authors.initials: M
authors.lastname: Sellers
authors.forename: John N
authors.initials: JN
authors.lastname: Stallone
authors.forename: Eric R
authors.initials: ER
authors.lastname: Prossnitz
authors.forename: Richard E
authors.initials: RE
authors.lastname: White
authors.forename: Guichun
authors.initials: G
authors.lastname: Han
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D003331:Coronary Vessels / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology; D004958:Estradiol / Q000494:pharmacology*; D006801:Humans; D051036:Large-Conductance Calcium-Activated Potassium Channels / Q000378:metabolism / Q000502:physiology; D009126:Muscle Relaxation / Q000187:drug effects* / Q000502:physiology; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000502:physiology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D011960:Receptors, Estrogen; D043562:Receptors, G-Protein-Coupled / Q000819:agonists* / Q000378:metabolism; D013552:Swine; D015854:Up-Regulation / Q000187:drug effects; D014664:Vasodilation / Q000502:physiology
chemical_list: C109584:GPER1 protein, human; D051036:Large-Conductance Calcium-Activated Potassium Channels; D011960:Receptors, Estrogen; D043562:Receptors, G-Protein-Coupled; D009569:Nitric Oxide; D004958:Estradiol; D002118:Calcium