Oestrogen receptor alpha in pulmonary hypertension

Wright, Audrey F.; Ewart, Marie-Ann; Mair, Kirsty M.; Nilsen, Margaret; Dempsie, Yvonne; Loughlin, Lynn; MacLean, Margaret R.

doi:10.1093/cvr/cvv106

Cited by 50 publications

(68 citation statements)

References 49 publications

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“…Our work is in agreement with previous works showing that ERα was involved in the protective effect of 17β‐estradiol against AngII‐induced hypertension 47. Interestingly, a protective role for ERα has been also suggested in pulmonary hypertension 48. The present study definitively demonstrates the role of ERα in this beneficial effect of endogenous estrogens independently on ERα MISS.…”

Section: Discussionsupporting

confidence: 93%

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: Discussionsupporting

confidence: 93%

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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“…We note that all previous work on sex bias in rodent-based PH models, including after administration of steroid sex hormones (for example, E2, 2-ME or testosterone) and/or gonadectomy, have focused on direct effects of steroid hormones at the level of peripheral vascular tissues in the lung (5,6,8,(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26). (However, the terminology used can often be confusing and, indeed, misleading.…”

Section: A Gap In Knowledge In the Ph Literature Concerning Sex Biasmentioning

confidence: 99%

“…Thus, in the context of a "neuroendocrine hypothesis," the term "central" refers to the hypothalamus and pituitary [the "neuro-" part], while the terms "distal" or "peripheral" refer to all locations in the body where a hormone can circulate [the "-endocrine" part]). Thus, there have been extensive studies of steroid hormone effects (E2, 2-ME, testosterone) in lung tissues in rodent models, in isolated human and rodent pulmonary vascular cells (smooth muscle cells [SMCs] and endothelial cells [ECs]) and on vascular cell proliferation, transcriptional regulation of BMPR2 gene expression and BMPR2-initiated cell signaling (5,6,8,(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26). This exclusive focus on peripheral tissue effects of steroid hormones is somewhat at odds with insights gleaned over the last 30-40 years in a sister field (sex-biased expres- Figure 1.…”

Section: A Gap In Knowledge In the Ph Literature Concerning Sex Biasmentioning

confidence: 99%

“…Although increased serotonin (5-HT) has been implicated in the pathogenesis of PH (10,15,26,100), especially in the femalespecific mouse models developed by MacLean et al (19)(20)(21), and after administration of an anorectic drug dexfenfluramine (22,100), the mechanistic focus has largely been on effects of 5-HT on distal vascular tissues (10,15,19-22,26,100). We note that it is already known that the PHcausing anorexigens fenfluramine, aminorex, phentermine and fluoxetine increase 5-HT in the hypothalamus (101)(102)(103)(104)(105) and that fenfluramine blunted GH responsiveness to GHRH (105).…”

Section: Synthesis Of the Literature On Sex Bias Mediated By The Neurmentioning

confidence: 99%

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Hypothesis: Neuroendocrine Mechanisms (Hypothalamus-Growth Hormone-STAT5 Axis) Contribute to Sex Bias in Pulmonary Hypertension

Sehgal

Yang

Miller

2015

Mol Med

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Pulmonary hypertension (PH) is a disease with high morbidity and mortality. The prevalence of idiopathic pulmonary arterial hypertension (IPAH) and hereditary pulmonary arterial hypertension (HPAH) is approximately two-to four-fold higher in women than in men. Paradoxically, there is an opposite male bias in typical rodent models of PH (chronic hypoxia or monocrotaline); in these models, administration of estrogenic compounds (for example, estradiol-17β [E2]) is protective. Further complexities are observed in humans ingesting anorexigens (female bias) and in rodent models, such as after hypoxia plus SU5416/Sugen (little sex bias) or involving serotonin transporter overexpression or dexfenfluramine administration (female bias). These complexities in sex bias in PH remain incompletely understood. We recently discovered that conditional deletion of signal transducer and activator of transcription 5a/b (STAT5a/b) in vascular smooth muscle cells abrogated the male bias in PH in hypoxic mice and that late-stage obliterative lesions in patients of both sexes with IPAH and HPAH showed reduced STAT5a/b, reduced Tyr-P-STAT5 and reduced B-cell lymphoma 6 protein (BCL6). In trying to understand the significance of these observations, we realized that there existed a wellcharacterized E2-sensitive central neuroendocrine mechanism of sex bias, studied over the last 40 years, that, at its peripheral end, culminated in species-specific male ("pulsatile") versus female ("more continuous") temporal patterns of circulating growth hormone (GH) levels leading to male versus female patterned activation of STAT5a/b in peripheral tissues and thus sex-biased expression of hundreds of genes. In this report, we consider the contribution of this neuroendocrine mechanism (hypothalamus-GH-STAT5) in the generation of sex bias in different PH situations.

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“…As examples, there is an extensive literature on the effects of E2 on increasing the function of eNOS in endothelial cells, the ability of E2 to stimulate vascular smooth muscle cell proliferation, and to inhibit the trafficking of vasorelevant receptors such as BMPR2 (bone morphogenetic receptor 2) to the cell surface. 6,[21][22][23][24][25][26][27][28] However, these studies of direct effects of sex hormones on vascular cells, taken together, have been unable to explain the many disparate sex bias observations in a vascular disease such as PH in humans and different rodent species.…”

Section: Introductionmentioning

confidence: 99%

STAT5a/b contribute to sex bias in vascular disease: A neuroendocrine perspective

et al. 2015

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ABSTRACT. Previous studies have elucidated a neuroendocrine mechanism consisting of the hypothalamus (growth hormone releasing hormone, GHRH) -pituitary (growth hormone, GH) -STAT5a/b axis that underlies sex-biased gene expression in the liver. It is now established that male vs female patterned secretion of GHRH, and thus of circulating GH levels ("pulsatile" vs "more continuous" respectively), leading to differently patterned activation of PY-STAT5a/b in hepatocytes results in sex-biased gene expression of cohorts of hundreds of downstream genes. This review outlines new data in support of a STAT5a/b-based mechanism of sex bias in the vascular disease pulmonary hypertension (PH). Puzzling observations in PH include its 2-4-fold higher prevalence in women but a male-dominance in many rodent models, and, paradoxically, inhibition of PH development by estrogens in such models. We observed that conditional deletion of STAT5a/b in vascular smooth muscle cells (SMC) in mice converted the male-dominant model of chronic hypoxia-induced PH into a female-dominant phenotype. In human idiopathic PH, there was reduced STAT5a/b and PY-STAT5 in cells in late-stage obliterative pulmonary arterial lesions in both men and women. A juxtaposition of the prior liver data with the newer PH-related data drew attention to the hypothalamus-GH-STAT5 axis, which is the major target of estrogens at the level of the hypothalamus. This hypothesis explains many of the puzzling aspects of sex bias in PH in humans and rodent models. The extension of STAT5-anchored mechanisms of sex bias to vascular disease emphasizes the contribution of central neuroendocrine processes in generating sexual dimorphism in different tissues and cell types.

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Oestrogen receptor alpha in pulmonary hypertension

Cited by 50 publications

References 49 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

Hypothesis: Neuroendocrine Mechanisms (Hypothalamus-Growth Hormone-STAT5 Axis) Contribute to Sex Bias in Pulmonary Hypertension

STAT5a/b contribute to sex bias in vascular disease: A neuroendocrine perspective

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