17β-Estradiol induces vasorelaxation in a G-protein-coupled receptor 30-independent manner

Seok, Young Mi; Jang, Eun Jin; Reiser, Oliver; Hager, Markus; Kim, In Kyeom

doi:10.1007/s00210-012-0770-y

Cited by 12 publications

(10 citation statements)

References 29 publications

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“…Research largely has focused upon GPR30 expression and the effect of agonism and antagonism in cancer cells (Filardo and Thomas, 2012), whereas our study examined its effects not associated to anti-mitogenic potentiation. 17-β-Estradiol, considered by many to be the endogenous ligand for this receptor, has been shown to induce vasodilatory effects (Meyer et al, 2011); however, a recent study found that 17-β-Estradiol induced vasodilation in rat aorta but was not prevented by the application of the GPR30 antagonist G15 (Seok et al, 2012). Interestingly, this study demonstrated that G1, applied in the same manner as 17-β-Estradiol, induced vasodilation, and this effect was reversible with the addition of G15, suggesting that GPR30 activation can result in relaxation of smooth muscle, and this effect is not mediated by 17-β-Estradiol.…”

Section: Discussionmentioning

confidence: 99%

2-Methoxyestradiol binding of GPR30 down-regulates angiotensin AT1 receptor

Koganti

Snyder

Gumaste

et al. 2014

European Journal of Pharmacology

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Controlling angiotensin AT1 receptor function has been shown to be protective for many pathophysiological disorders. Although estrogen metabolite, 2-methoxyestradiol (2ME2) can down-regulate angiotensin AT1 receptor expression independently of nuclear receptors, no specific cellular targets have been identified. This study was focused on identification and validation of a cellular target responsible for 2ME2-mediated angiotensin AT1 receptor down-regulation in a continuously passaged rat liver epithelial cell line. Cell membranes were isolated and used to determine 2ME2 specific binding. Cell membranes exposed to [3H]2ME2 showed specific saturable binding, which was found to be pertussis toxin (PTx) sensitive. Under similar conditions, G-protein coupled receptor 30 (GPR30) agonist (G1) and antagonist (G15) inhibited 2ME2 specific binding. In these cells GPR30 was found localized to endoplasmic reticulum (ER) membranes. In intact cells, G1 down-regulated angiotensin AT1 receptor expression and this effect was reversed by G15. Furthermore, 2ME2 mediated activation of epidermal growth factor receptor (EGFR) followed by ERK1/2 phosphorylation, an essential signaling step in angiotensin AT1 receptor down-regulation, was abrogated by G15, suggesting that this signal is GPR30 dependent. Additionally, EGF was found to independently down-regulate angiotensin AT1 receptor in an ERK1/2-dependent manner. In summary, our results demonstrate for the first time that 2ME2 down-regulation of angiotensin AT1 receptor is dependent on ER membrane-associated GRP30. Moreover, this effect is facilitated by GPR30 dependent transactivation of EGFR and ERK1/2 phosphorylation. This study provides further understanding of the physiological significance of 2ME2 and its role in modulating angiotensin AT1 receptor expression.

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Section: Discussionmentioning

confidence: 99%

2-Methoxyestradiol binding of GPR30 down-regulates angiotensin AT1 receptor

Koganti

Snyder

Gumaste

et al. 2014

European Journal of Pharmacology

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“…ER‐α mediates a number of the vasoprotective effects of oestrogen including endothelial cell proliferation, vascular re‐endothelialization and production of endothelial NO . However, several studies have reported that GPER‐1 is independent of ER . G1 mediates vasorelaxation through activation of GPER‐1, but has no detectable activity towards the classical ERs .…”

Section: Discussionmentioning

confidence: 99%

“…[30][31][32] However, several studies have reported that GPER-1 is independent of ER. [12,33,34] G1 mediates vasorelaxation through activation of GPER-1, but has no detectable activity towards the classical ERs. [6] Pretreatment with a GPER-1 antagonist, G15, but not a general ER antagonist, ICI 182 780, or an ER-a-selective antagonist, MPP, resulted in attenuated endothelium-dependent vasorelaxation induced by G1 (Figure 1), indicating that endothelium-dependent vasorelaxation by G1 does not mediate oestrogen receptor (Figure 3).…”

Section: Discussionmentioning

confidence: 99%

GPER-1 agonist G1 induces vasorelaxation through activation of epidermal growth factor receptor-dependent signalling pathway

Jang

Seok

Arterburn

et al. 2013

Journal of Pharmacy and Pharmacology

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“…In some experiments, endothelium denudation or treatment with the NOS inhibitor L‐NAME reduces G‐1‐induced vasodilatation , suggesting that G‐1‐evoked vasorelaxation involves nitric oxide. However, in other experiments, G‐1 still dilates isolated vessels if endothelium is removed or if the vascular preparations are treated with L‐NAME, suggesting that other mechanisms besides nitric oxide are also involved . Thus, further investigations are needed to clarify the importance of endothelial nitric oxide for GPR30‐mediated vascular relaxation.…”

Section: Oestrogen and Blood Pressurementioning

confidence: 95%

Identification and Characterization of New Mechanisms in Vascular Oestrogen Signalling

Holm

Nilsson

2013

Basic Clin Pharma Tox

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Oestrogen exerts vasculoprotective effects in different experimental settings through inhibition of vascular smooth muscle cell proliferation, stimulation of nitric oxide production and attenuation of inflammation. Although these oestrogen-evoked beneficial effects have been attributed to oestrogen receptor alpha (ERa), also ER beta (ERb) and the novel ER G protein-coupled receptor 30 (GPR30)/G protein-coupled ER1 probably play significant roles in vascular oestrogen signalling. Oestrogenevoked vasculoprotective effects are well documented in various experimental models, but the underlying mechanisms are still incompletely understood. The age hypothesis represents an interesting and promising model to explain the discrepancy between experimental data showing beneficial vascular effects of oestrogen treatment and the clinical findings on hormone replacement therapy obtained in big epidemiology surveys, where no protective effect from supplementation with oestrogen is observed. Identification of novel ERs expressed also in the vascular system offers exciting opportunities for the future to find and characterize the mechanisms behind oestrogen-evoked beneficial effects in vascular health and disease. Importantly, some vascular effects of pharmacological concentrations of oestrogen are ER-independent, suggesting that oestrogen besides its specific effects through ERa, ERb and GPR30 also affects vascular function via ER-independent mechanisms probably reflecting interaction of the hydrophobic oestrogen molecule with cell membrane properties. In this MiniReview, we focus on the importance of these different vascular ER subtypes in health and disease. Cardiovascular Disease and OestrogenDespite improved treatment and awareness, cardiovascular disease and its complications like stroke and myocardial infarction remain the leading cause of death and morbidity in the world. With an increasingly older population in both old developed nations and the developing world, the number of patients suffering from cardiovascular disease will probably increase further during the 21st century. The acute symptoms of cardiovascular disease, like transient ischaemic attack, are commonly initiated by embolism or luminal narrowing of the arteries due to excessive growth of vascular smooth muscle cells. This is in turn initiated by high concentrations of lowdensity lipoproteins in the blood accumulating subendothelially and high blood pressure, respectively Oestrogen possesses atheroprotective effects, observed in premenopausal women being less prone to cardiovascular disease than age-matched men [1]. On average, cardiovascular disease starts 10 years later in women than men and before menopause women have several times lower risk than men [2]. This difference disappears quickly after menopause. Because of this, post-menopausal oestrogen supplementation was believed to have vasculoprotective effects [3]. However, the largest study of the effect of oestrogen supplementation in post-menopausal women, the 2002 Women's Health Initiativ...

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17β-Estradiol induces vasorelaxation in a G-protein-coupled receptor 30-independent manner

Cited by 12 publications

References 29 publications

2-Methoxyestradiol binding of GPR30 down-regulates angiotensin AT1 receptor

2-Methoxyestradiol binding of GPR30 down-regulates angiotensin AT1 receptor

GPER-1 agonist G1 induces vasorelaxation through activation of epidermal growth factor receptor-dependent signalling pathway

Identification and Characterization of New Mechanisms in Vascular Oestrogen Signalling

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