Ligand-dependent activation of ER  lowers blood pressure and attenuates cardiac hypertrophy in ovariectomized spontaneously hypertensive rats

Jazbutyte, Virginija; Arias-Loza, Paula; Hu, Kai; Widder, Julian; Govindaraj, Vijayakumar; Poser-Klein, Christine von; Bauersachs, Johann; Fritzemeier, Karl Heinrich; Hegele‐Hartung, Christa; Neyses, Ludwig; Ertl, Georg; Pelzer, Theo

doi:10.1093/cvr/cvm081

Cited by 73 publications

(51 citation statements)

References 36 publications

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“…Indeed, basal arterial blood pressure increases more in ERβ −/− mice during aging than in age‐matched control mice 49. In addition, the pharmacological activation of ERβ leads to blood pressure lowering in spontaneously hypertensive rats with reduced myocardial hypertrophy 50. Arias‐Loza et al also show that both ERα and ERβ activation attenuates cardiovascular remodeling in aldosterone salt‐treated rats 51.…”

Section: Discussionmentioning

confidence: 99%

Predominant Role of Nuclear Versus Membrane Estrogen Receptor α in Arterial Protection: Implications for Estrogen Receptor α Modulation in Cardiovascular Prevention/Safety

Guivarch

Buscato

Guihot

et al. 2018

JAHA

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BackgroundAlthough estrogen receptor α (ERα) acts primarily as a transcription factor, it can also elicit membrane‐initiated steroid signaling. Pharmacological tools and transgenic mouse models previously highlighted the key role of ERα membrane‐initiated steroid signaling in 2 actions of estrogens in the endothelium: increase in NO production and acceleration of reendothelialization.Methods and ResultsUsing mice with ERα mutated at cysteine 451 (ERaC451A), recognized as the key palmitoylation site required for ERα plasma membrane location, and mice with disruption of nuclear actions because of inactivation of activation function 2 (ERaAF20 = ERaAF2°), we sought to fully characterize the respective roles of nuclear versus membrane‐initiated steroid signaling in the arterial protection conferred by ERα. ERaC451A mice were fully responsive to estrogens to prevent atheroma and angiotensin II–induced hypertension as well as to allow flow‐mediated arteriolar remodeling. By contrast, ERαAF20 mice were unresponsive to estrogens for these beneficial vascular effects. Accordingly, selective activation of nuclear ERα with estetrol was able to prevent hypertension and to restore flow‐mediated arteriolar remodeling.ConclusionsAltogether, these results reveal an unexpected prominent role of nuclear ERα in the vasculoprotective action of estrogens with major implications in medicine, particularly for selective nuclear ERα agonist, such as estetrol, which is currently under development as a new oral contraceptive and for hormone replacement therapy in menopausal women.

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Section: Discussionmentioning

confidence: 99%

Predominant Role of Nuclear Versus Membrane Estrogen Receptor α in Arterial Protection: Implications for Estrogen Receptor α Modulation in Cardiovascular Prevention/Safety

Guivarch

Buscato

Guihot

et al. 2018

JAHA

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“…Rapid signaling by estrogen also prevents aspects of atherosclerosis in cells from animal models (62). Several groups have shown that ER␤ mediates the ability of estrogen to prevent cardiac hypertrophy that results from G q ␣ signaling by angiotensin II (Ang II) (2), genetic hypertension (17), or pulmonary hypertension (27). We have shown that membrane ER␤ signaling prevents the activation of calcineurin by Ang II or endothelin-1 (43).…”

Section: Impact Of Membrane Er For Protection Against Cardiovascular mentioning

confidence: 99%

Extranuclear estrogen receptor's roles in physiology: lessons from mouse models

Levin

2014

American Journal of Physiology-Endocrinology and Metabolism

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Levin ER. Extranuclear estrogen receptor's roles in physiology: lessons from mouse models. Am J Physiol Endocrinol Metab 307: E133-E140, 2014. First published June 3, 2014 doi:10.1152/ajpendo.00626.2013.-Steroid receptors exist and function in multiple compartments of cells in most organs. Although the functions and nature of some of these receptors is being defined, important aspects of receptor localization and signaling to physiology and pathophysiology have been identified. In particular, extranuclear sex steroid receptors have been found in many normal cells and in epithelial tumors, where they enact signal transduction that impacts both nongenomic and genomic functions. Here, I focus on the progress made in understanding the roles of extranuclear estrogen receptors (ER) in physiology and pathophysiology. Extranuclear ER serve as a model to selectively intervene with novel receptor reagents to prevent or limit disease progression. Recent novel mouse models and membrane ER-selective agonists also provide a better understanding of receptor pool cross-talk that results in the overall integrative actions of sex steroids. membrane estrogen receptor; signal transduction; steroid receptors MORE THAN HALF A CENTURY AGO, the eminent endocrinologist Hans Selye first described rapid actions of steroid hormones in mammals (58). Rapid actions of glucocorticoids in vascular models were not consistent with the emerging field of gene regulation by nuclear steroid receptors. Because of technological limitations, the mediators of these rapid actions of glucocorticoids were not defined in that period. In contrast, in the 1960s and 1970s, Pietras and Szego (48,49), along with Szego and Davis (59), described rapid actions of estrogen, including calcium flux and cAMP generation that occurred in seconds after exposure of cells to this steroid. These authors provided evidence of estrogen binding to a presumed receptor, possibly at the cell surface, but the nature of this probable binding protein was unknown. These observations were consistent with the later description and isolation of a membrane protein that served as a receptor for plant brassinosteroids, bona fide steroids that mediate flowering and fertility. The brassinosteroid receptor was found to be a plasma membrane tyrosine kinase (64), establishing that the ancient and conserved function of steroids from plants to humans results from actions at the membrane. These rapid signals seemed unlikely to emanate from nuclear receptors, whose transcriptional function was defined as being much slower.Today, we know that the distribution of steroid receptors in vertebrates favors nuclear localization. Increased genome complexity occurs as one moves up the phylogenetic order and probably provides the impetus for evolution to create nuclear pools of steroid receptors. This allows binding of these receptors to promoters and especially multiple steroid response elements at enhancer DNA throughout the genome of many cells, regulating gene expression that is necessary for normal develo...

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“…4 Furthermore, activation of ERβ improved nitric oxide-dependent vasorelaxation, increased cardiac output, and attenuated cardiac hypertrophy; however, this study did not determine whether these effects were peripherally or centrally mediated.…”

mentioning

confidence: 77%

“…3 Pharmacological studies supported these conclusions by demonstrating selective agonists of ERβ-reduced arterial pressure in ovariectomized spontaneously hypertensive rats under conditions in which ERα-selective agonists did not. 4 Furthermore, activation of ERβ improved nitric oxide-dependent vasorelaxation, increased cardiac output, and attenuated cardiac hypertrophy; however, this study did not determine whether these effects were peripherally or centrally mediated.…”

mentioning

confidence: 77%

“…Moreover, a study in ovariectomized spontaneously hypertensive rats demonstrated that an ERβ agonist was more effective than E 2 at lowering blood pressure while simultaneously avoiding the uterine growth-promoting effects of E 2 . 4 Thus, it is conceivable that an ER-selective agonist could be developed that activated ERβ in key brain nuclei without exerting unwanted peripheral effects in men.…”

Section: Hypertensionmentioning

confidence: 99%

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Is β the α Dog in Estrogen Receptor–Mediated Protection From Hypertension?

Sandberg

2013

Hypertension

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T he onset of hypertension occurs earlier in men than in women. Moreover, the magnitude of hypertension is greater in men than in women across diverse mammalian species and experimental models. 1 17β-estradiol (E 2 ) is implicated in this female protection because ovarian hormone loss is associated with increased arterial pressure while E 2 replacement can prevent this effect. Creation of mice deficient in estrogen receptors (ERα and ERβ) and the development of ER subtypeselective ligands have enabled investigation of ER subtypes in hypertension.A study of Japanese women revealed an association between hypertension and a cytosine-adenine repeat polymorphism in the ERβ gene.2 This association was strengthened by studies in ERβ-deficient mice, which developed hypertension as they aged and exhibited abnormal ion channel function in vascular smooth muscle cells suggesting ERβ attenuated the age-associated hypertension by preserving vascular function.3 Pharmacological studies supported these conclusions by demonstrating selective agonists of ERβ-reduced arterial pressure in ovariectomized spontaneously hypertensive rats under conditions in which ERα-selective agonists did not. 4 Furthermore, activation of ERβ improved nitric oxide-dependent vasorelaxation, increased cardiac output, and attenuated cardiac hypertrophy; however, this study did not determine whether these effects were peripherally or centrally mediated.Previously, Xue et al 5 showed that central but not peripheral infusions of a nonselective ER antagonist into mice augmented the pressor effects of angiotensin II (Ang II), thereby underscoring the importance of central ERs in blood pressure modulation. In this issue, Xue et al 6 used small interference RNA via an adeno-associated virus to selectively knockdown ERα and ERβ in specific brain nuclei. Mice with ERβ deficiency in the paraventricular nucleus (PVN) and rostral ventrolateral medulla (RVLM) exhibited increased sympathetic activity during mineralocorticoid excess. In contrast, ERα knockdown in these same nuclei had no effect on sympathetic activity during aldosterone treatment and sodium loading. In addition, they showed that pharmacological activation of neuronal ERβ but not ERα reduced arterial pressure under these conditions. Using this complementary approach, they addressed a caveat associated with nuclei-specific siRNA technology, namely, that remaining ERα after incomplete knockdown may be sufficient to mimic the actions of the ERα-replete wild-type mice. These findings elegantly demonstrate ERβ-specific effects on central autonomic control of arterial pressure during mineralocorticoid excess.The authors propose that inhibition of superoxide anion in the PVN contributes to the antihypertensive effects of ERβ on the basis of observing augmented superoxide anion formation after silencing ERβ in cultured PVN neurons treated overnight with aldosterone; however, these ER-observed effects on superoxide generation occurred in the absence of E 2 and were ER subtype independent. These cell culture stu...

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Ligand-dependent activation of ER lowers blood pressure and attenuates cardiac hypertrophy in ovariectomized spontaneously hypertensive rats

Abstract: Ligand-dependent activation of ERbeta confers blood pressure lowering effects in SHR that are superior to those of 17beta-estradiol or the ERalpha agonist 16alpha-LE2 and attenuates cardiac hypertrophy primarily by a reduction of cardiac afterload without promoting uterine growth.

Cited by 73 publications

References 36 publications

Predominant Role of Nuclear Versus Membrane Estrogen Receptor α in Arterial Protection: Implications for Estrogen Receptor α Modulation in Cardiovascular Prevention/Safety

Predominant Role of Nuclear Versus Membrane Estrogen Receptor α in Arterial Protection: Implications for Estrogen Receptor α Modulation in Cardiovascular Prevention/Safety

Extranuclear estrogen receptor's roles in physiology: lessons from mouse models

Is β the α Dog in Estrogen Receptor–Mediated Protection From Hypertension?

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