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. 2011 Nov;301(5):E882-8.
doi: 10.1152/ajpendo.00037.2011. Epub 2011 Jul 26.

Activation of G protein-coupled estrogen receptor induces endothelium-independent relaxation of coronary artery smooth muscle

Xuan Yu  1 , Handong Ma, Scott A Barman, Alexander T Liu, Minga Sellers, John N Stallone, Eric R Prossnitz, Richard E White, Guichun Han
Affiliations

Activation of G protein-coupled estrogen receptor induces endothelium-independent relaxation of coronary artery smooth muscle

Xuan Yu et al. Am J Physiol Endocrinol Metab. 2011 Nov.

Erratum in

  • Am J Physiol Endocrinol Metab. 2012 Dec 15;303(12):E1502-3

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.

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Figures

Fig. 1.
Fig. 1.
Stimulation of G protein-coupled estrogen receptor 1 (GPER) relaxes endothelium-denuded, precontracted coronary arteries. A: complete concentration-response relationship for G-1-induced relaxation. Each point represents the mean relaxation effect ± SE (n = 29). Top curve is a control concentration-response relationship in the presence of solvent (DMSO) alone (n = 6). B: actual G-1-induced relaxation response after normalization by subtracting the control component. C: complete concentration-response relationship for G-1-induced relaxation in the presence (○) or absence (■) of G15, a GPER antagonist. Each point represents the mean relaxation effect ± SE (n = 21). *P < 0.05.
Fig. 2.
Fig. 2.
Coronary artery smooth muscle (CASM) cells express GPER. A: GPER mRNA is expressed in porcine and human CASM. RT-PCR products from MCF-7 cells were employed as positive controls. B: immunoblot detection of GPER protein expression in coronary myocytes from either porcine (P) or human (H) arteries (n = 3). MCF-7 cells were employed as positive controls. β-Actin was employed as a control for protein loading.
Fig. 3.
Fig. 3.
GPER-mediated coronary artery relaxation is nitric oxide independent and involves large-conductance, calcium-activated potassium (BKCa) channel activity. A: pretreating (30 min) coronary arteries with 100 μM Nω-nitro-l-arginine methyl ester (l-NAME) to inhibit nitric oxide synthase had no effect on G-1-induced relaxation. Each bar represents the mean ± SE (n = 6) B: pretreating vessels (30 min) with 100 nM iberiotoxin (IBTx; 30 min; n = 5) attenuated 1 μM G-1-induced relaxation significantly (*P = 0.001). C: complete concentration-response relationship for G-1-induced relaxation in the absence (■) or presence (○) of 100 nM IBTx (n = 5). *P < 0.05 or lower. Con, control.
Fig. 4.
Fig. 4.
G-1 stimulates BKCa channel activity in porcine CASM cells. A: typical recordings from the same cell-attached patch (+40 mV) before (con) and 20 minutes after application of 100 nM G-1. Upward deflections indicate channel opening from the closed state (dashed line). Right: activity histogram of BKCa channel open probability (NPo) before and 20 minutes after application of 100 nM G-1. Total recording time under each condition was 12–14 s. Break in the time axis represents drug incubation. B: typical recordings from the same excised inside-out patch from a porcine CASM cell with either 100 nM (left) or 100 μM (middle) [Ca2+] exposed to the cytoplasmic face of the membrane (+40 mV). Right: recording after subsequent addition of 1 mM tetraethylammonium (TEA) to the cytoplasmic surface of the membrane (100 μM [Ca2+]).
Fig. 5.
Fig. 5.
G-1 stimulates BKCa channel activity in human CASM cells. A: recordings (+40 mV) from the same cell-attached patch on human CASM cells before (control) and 25 min after addition of 100 nM G-1. Upward deflections indicate channel opening from the closed state (dashed line). Right: average increase in BKCa channel activity (NPo) stimulated by G-1. Bars represent the average of 3 membrane patches ± SE. B: recordings from the same excised inside-out patch from human CASM cells. Upward deflections indicate channel opening from the closed state (dashed line). Left: BKCa channel activity in the presence of high calcium (100 μM) at the cytoplasmic surface of the patch. Middle: channel activity recorded after calcium levels were lowered to 100 nM. Right: G-1 (100 nM) had no effect on channel activity in excised patch. *P < 0.05.
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