Obligatory role for GPER in cardiovascular aging and disease

Meyer, Matthias R.; Fredette, Natalie C.; Daniel, Christoph; Sharma, Geetanjali; Amann, Kerstin; Arterburn, Jeffrey B.; Barton, Matthias; Prossnitz, Eric R.

doi:10.1126/scisignal.aag0240

Cited by 62 publications

(76 citation statements)

References 83 publications

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“…Gper −/− mice were generated and backcrossed as described [12]. Wild-type C57BL/6 and Gper −/− mice were housed at the Animal Resource Facility of the University of New Mexico Health Sciences Center under controlled temperature (22 °C) on a 12-hour light-dark cycle with unrestricted access to water and a rodent diet devoid of alfalfa or soybean meal to minimize the presence of natural phytoestrogens (Teklad 2020SX, Harlan Laboratories, Madison, WI).…”

Section: Methodsmentioning

confidence: 99%

“…In subsequent experiments, the role of NADPH oxidase was studied by randomly treating the left or right renal artery with the Nox1/2-selective inhibitor gp91ds-tat (3 μmol/L for 30 minutes) [15]. This peptide is derived from a gp91 phox (now termed Nox2) sequence in the region that interacts with the organizer protein p47 phox , thus disrupting p47 phox binding to and activation of the homologous Nox2 and Nox1 catalytic subunits [7, 12]. To study endothelium-dependent, NO-mediated relaxations, arteries were precontracted with phenylephrine to ~70% of KCl-induced contractions, and responses to acetylcholine (0.1 nmol/L – 10 μmol/L) were recorded.…”

Section: Methodsmentioning

confidence: 99%

“…We have recently identified an unexpected role of a constitutively active GPCR termed GPER, a heptahelical transmembrane receptor that also signals via estrogen-dependent mechanisms [11], which facilitates Nox1 expression and activity in the aorta and hearts of aged mice, as well as in human aortic smooth muscle cells [12]. Ligand-independent GPER activity was also found to mediate Nox1-dependent impaired vascular function in arterial hypertension [12], however, whether GPER contributes to age-dependent functional changes of renal arteries is unknown.…”

Section: Introductionmentioning

confidence: 99%

“…Ligand-independent GPER activity was also found to mediate Nox1-dependent impaired vascular function in arterial hypertension [12], however, whether GPER contributes to age-dependent functional changes of renal arteries is unknown.…”

Section: Introductionmentioning

confidence: 99%

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GPER Mediates Functional Endothelial Aging in Renal Arteries

Meyer¹,

Rosemann²,

Barton³

et al. 2017

Pharmacology

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Aging is associated with impaired renal artery function, which is partly characterized by arterial stiffening and a reduced vasodilatory capacity due to excessive generation of reactive oxygen species by NADPH oxidases (Nox). The abundance and activity of Nox depends on basal activity of the heptahelical transmembrane receptor GPER; however, whether GPER contributes to age-dependent functional changes in renal arteries is unknown. This study investigated the effect of aging and Nox activity on renal artery tone in wild-type and GPER-deficient (Gper^-/-) mice (4 and 24 months old). In wild-type mice, aging markedly impaired endothelium-dependent, nitric oxide (NO)-mediated relaxations to acetylcholine, which were largely preserved in renal arteries of aged Gper^-/- mice. The Nox inhibitor gp91ds-tat abolished this difference by greatly enhancing relaxations in wild-type mice, while having no effect in Gper^-/- mice. Contractions to angiotensin II and phenylephrine in wild-type mice were partly sensitive to gp91ds-tat but unaffected by aging. Again, deletion of GPER abolished effects of Nox inhibition on contractile responses. In conclusion, basal activity of GPER is required for the age-dependent impairment of endothelium-dependent, NO-mediated relaxation in the renal artery. Restoration of relaxation by a Nox inhibitor in aged wild-type but not Gper^-^/- mice strongly supports a role for Nox-derived reactive oxygen species as the underlying cause. Pharmacological blockers of GPER signaling may thus be suitable to inhibit functional endothelial aging of renal arteries by reducing Nox-derived oxidative stress and, possibly, the associated age-dependent deterioration of kidney function.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

GPER Mediates Functional Endothelial Aging in Renal Arteries

Meyer¹,

Rosemann²,

Barton³

et al. 2017

Pharmacology

Self Cite

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“…As estrogen receptor in the cardiovascular system, it influences vascular tone through modulation of p-eNOS/ eNOS and pERK/ERK ratios as well as apoptosis via PI3K, c-SRC and EGFR and also influences PKA (Filardo et al 2000, Meyer et al 2016. A protective role in pulmonary hypertension, atherosclerosis and diabetes has been postulated (Barton & Prossnitz 2015, Prossnitz & Hathaway 2015.…”

Section: Gper1mentioning

confidence: 99%

30 YEARS OF THE MINERALOCORTICOID RECEPTOR: Nongenomic effects via the mineralocorticoid receptor

Ruhs

Nolze

Hübschmann

et al. 2017

Journal of Endocrinology

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The mineralocorticoid receptor (MR) belongs to the steroid hormone receptor family and classically functions as a ligand-dependent transcription factor. It is involved in water-electrolyte homeostasis and blood pressure regulation but independent from these effects also furthers inflammation, fibrosis, hypertrophy and remodeling in cardiovascular tissues. Next to genomic effects, aldosterone elicits very rapid actions within minutes that do not require transcription or translation and that occur not only in classical MR epithelial target organs like kidney and colon but also in nonepithelial tissues like heart, vasculature and adipose tissue. Most of these effects can be mediated by classical MR and its crosstalk with different signaling cascades. Near the plasma membrane, the MR seems to be associated with caveolin and striatin as well as with receptor tyrosine kinases like EGFR, PDGFR and IGF1R and G proteincoupled receptors like AT1 and GPER1, which then mediate nongenomic aldosterone effects. GPER1 has also been named a putative novel MR. There is a close interaction and functional synergism between the genomic and the nongenomic signaling so that nongenomic signaling can lead to long-term effects and support genomic actions. Therefore, understanding nongenomic aldosterone/MR effects is of potential relevance for modulating genomic aldosterone effects and may provide additional targets for intervention.

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G-Protein-Coupled Estrogen Receptor (GPER) and Sex-Specific Metabolic Homeostasis

Sharma

Prossnitz

2017

Advances in Experimental Medicine and Biology

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Obesity and metabolic syndrome display disparate prevalence and regulation between males and females. Human, as well as rodent, females with regular menstrual/estrous cycles exhibit protection from weight gain and associated chronic diseases. These beneficial effects are predominantly attributed to the female hormone estrogen, specifically 17β-estradiol (E2). E2 exerts its actions via multiple receptors, nuclear and extranuclear estrogen receptor (ER) α and ERβ, and the G-protein-coupled estrogen receptor (GPER, previously termed GPR30). The roles of GPER in metabolic homeostasis are beginning to emerge but are complex and remain unclear. The discovery of GPER-selective pharmacological agents (agonists and antagonists) and the availability of GPER knockout mice have significantly enhanced our understanding of the functions of GPER in normal physiology and disease. GPER action manifests pleiotropic effects in metabolically active tissues such as the pancreas, adipose, liver, and skeletal muscle. Cellular and animal studies have established that GPER is involved in the regulation of body weight, feeding behavior, inflammation, as well as glucose and lipid homeostasis. GPER deficiency leads to increased adiposity, insulin resistance, and metabolic dysfunction in mice. In contrast, pharmacologic stimulation of GPER in vivo limits weight gain and improves metabolic output, revealing a promising novel therapeutic potential for the treatment of obesity and diabetes.

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Obligatory role for GPER in cardiovascular aging and disease

Cited by 62 publications

References 83 publications

GPER Mediates Functional Endothelial Aging in Renal Arteries

GPER Mediates Functional Endothelial Aging in Renal Arteries

30 YEARS OF THE MINERALOCORTICOID RECEPTOR: Nongenomic effects via the mineralocorticoid receptor

G-Protein-Coupled Estrogen Receptor (GPER) and Sex-Specific Metabolic Homeostasis

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