17β-Estradiol Attenuates Hypoxic Pulmonary Hypertension via Estrogen Receptor–mediated Effects

Lahm, Tim; Albrecht, Marjorie; Fisher, Amanda; Selej, Mona; Patel, Neel; Brown, Jennifer; Justice, Matthew J.; Brown, Mary Beth; Demark, Mary Van; Trulock, Kevin; Dieudonne, Dino; Reddy, Jagadeshwar G.; Presson, Robert G.; Petrache, Irina

doi:10.1164/rccm.201107-1293oc

Cited by 147 publications

(205 citation statements)

References 76 publications

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“…The data from this study strongly support the notion that the rescue action of E 2 is mainly mediated through ER-b in MCT-induced PH [22]. LAHM et al [23] reported that a non-selective ER inhibitor and ER-a-and ER-b-specific antagonists opposed the effects of E 2 ; however, they considered that the important effects of E 2 on functional end-points in hypoxic PH were predominantly mediated by ER-a. Therefore, evaluation of ER expression in PH was considered important.…”

Section: Discussionsupporting

confidence: 85%

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Oestradiol ameliorates monocrotaline pulmonary hypertensionviaNO, prostacyclin and endothelin-1 pathways

Yuan

Gao³

et al. 2012

Eur Respir J

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Pulmonary hypertension continues to be a serious clinical problem with high mortality. As oestrogen is a potential vasodilator of the pulmonary circulation, this study examined the mechanisms by which 17b-oestradiol improves monocrotaline (MCT)-induced pulmonary hypertension.Female Sprague-Dawley rats underwent bilateral ovariectomy or sham operations. The rats received MCT (50 mg?kg -1 ) and were treated with 17b-oestradiol (1 mg?kg -1 per day) for either 5 weeks or only from week 4 to week 5. Plasma 17b-oestradiol concentrations were decreased in sham-operated, MCT-treated rats when compared with sham-operated rats (17.7¡4.7 versus 50.3¡15.4 pg?mL -1 ; p50.029). The 17b-oestradiol anabolic enzyme cytochrome P450 (CYP)-19 was decreased by MCT treatment, while the catabolic enzymes CYP-1A1 and -1B1 were increased. Ovariectomised and MCT-treated rats had more severe pulmonary hypertension. 17b-oestradiol suppressed pulmonary arterial smooth muscle cell proliferation and macrophage infiltration, and enhanced apoptosis by increasing nitric oxide (NO) and prostacyclin (prostaglandin (PG)I 2 ) levels and reducing endothelin (ET)-1 levels. Phosphoinositide-3-kinase (PI3K) and Akt phosphorylations were markedly increased, but were inhibited by 17b-oestradiol treatment in rats with pulmonary hypertension. Oestrogen deficiency may aggravate development of pulmonary hypertension. 17b-oestradiol improved pulmonary hypertension via activation of the PI3K/Akt pathway to regulate NO, PGI 2 and ET-1 expression.

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Section: Discussionsupporting

confidence: 85%

“…Therefore, evaluation of ER expression in PH was considered important. The data of LAHM et al [23] indicate that hypoxia increased ER-b, but not ER-a, lung vascular expression. In contrast, our results showed that MCT inhibited ER-a, but had no effect on ER-b proteins in the lung.…”

Section: Discussionmentioning

confidence: 92%

Oestradiol ameliorates monocrotaline pulmonary hypertensionviaNO, prostacyclin and endothelin-1 pathways

Yuan

Gao³

et al. 2012

Eur Respir J

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“…This hypothesis was explored in a study by LAHM et al [74] which demonstrated that E2 attenuates the decline in haemodynamic and remodelling parameters observed in hypoxia-induced PH in rats. In this model, the benefits of E2 are mediated by the oestrogen receptor and conversion to E2 metabolites is not required [74]. However, a protective role for E2 in human PAH has yet to be demonstrated.…”

Section: Oestrogen Signallingmentioning

confidence: 99%

“…As such, this pathway may be another potential therapeutic target. Despite evidence to support the benefits of E2 in rat hypoxia-induced PH [74], the strong female predominance in human PAH makes E2 less appealing as a potential therapy as there are concerns that E2 may promote PAH in humans. Instead, targeting the pathways downstream of E2, e.g.…”

Section: Oestrogen Signallingmentioning

confidence: 99%

Pathobiology of pulmonary arterial hypertension: understanding the roads less travelled

Hemnes

Humbert

2017

Eur Respir Rev

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The pathobiology of pulmonary arterial hypertension (PAH) is complex and incompletely understood. Although three pathogenic pathways have been relatively well characterised, it is widely accepted that dysfunction in a multitude of other cellular processes is likely to play a critical role in driving the development of PAH. Currently available therapies, which all target one of the three well-characterised pathways, provide significant benefits for patients; however, PAH remains a progressive and ultimately fatal disease. The development of drugs to target alternative pathogenic pathways is, therefore, an attractive proposition and one that may complement existing treatment regimens to improve outcomes for patients. Considerable research has been undertaken to identify the role of the less well-understood pathways and in this review we will highlight some of the key discoveries and the potential for utility as therapeutic targets.

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“…Oestrogen effects are therefore highly context and compartment specific. For example, E2 has been shown to stimulate pulmonary artery smooth muscle cell proliferation but to exert anti-proliferative effects in pulmonary artery endothelial cells [6][7][8]31]. Similarly, in a recent microarray analysis of lungs from chronically hypoxic rats treated with E2, the E2-regulated genome indicated that E2 regulates multiple genes whose activation or inhibition is consistent with anti-proliferative effects, but that E2 also induces changes consistent with pro-proliferative or pro-angiogenic effects [32].…”

mentioning

confidence: 99%

Inhibiting oestrogen signalling in pulmonary arterial hypertension: sex, drugs and research

Lahm

Kawut

2017

Eur Respir J

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@ERSpublicationsInhibition of oestrogen signalling in PAH is currently being studied clinically but several questions remain http://ow.ly/G7xK30cPN5MCite this article as: Lahm T, Kawut SM. Inhibiting oestrogen signalling in pulmonary arterial hypertension: sex, drugs and research. Eur Respir J 2017; 50: 1700983 [https://doi.org/10.1183/ 13993003.00983-2017.Pulmonary arterial hypertension (PAH) is a sexually dimorphic disease that affects women more than men. Several pre-clinical and clinical studies identified 17β-oestradiol (E2), the most abundant female sex hormone, and/or its metabolite 16α-hydroxyoestrone as disease mediators in PAH (reviewed by LAHM et al. E2 is mostly synthesised through aromatisation of androgens by the enzyme aromatase (encoded by the CYP19A1 gene). In females, this process primarily occurs in the ovaries, though later in life, extragonadal E2 production (e.g. in adipocytes) becomes the predominant source (as it is in males throughout life). Classical E2 signalling is characterised by activation of the oestrogen receptors ERα and/or ERβ, which translocate to the nucleus and act as transcription factors by binding to oestrogen response elements of target genes (reviewed by MURPHY [4]). However, several variations of this pathway exist, including nongenomic signalling and signalling through an orphan G-protein coupled receptor [1,4]. Aromatase and oestrogen receptors are found in both sexes and in every major organ system (including the lung and the right ventricle [5-8]), implying that oestrogens can have biologically relevant effects throughout the body.Preclinical and clinical studies implicate aromatase as a potential contributor to PAH pathogenesis [6,9]. Similarly, oestrogen receptor-mediated signalling has been linked to PAH development [8]. These studies have led to a recently published, small phase II randomised clinical trial (RCT) of aromatase inhibition with anastrozole in postmenopausal women and men with PAH [10]. This study demonstrated that anastrozole decreased serum E2 levels by 40% and increased 6-min walk distance, leading the authors to conclude that anastrozole therapy appeared safe and warranted further evaluation. Based on these results, a

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17β-Estradiol Attenuates Hypoxic Pulmonary Hypertension via Estrogen Receptor–mediated Effects

Abstract: E2 attenuates hemodynamic and remodeling parameters in HPH in an ER-dependent manner, through direct antiproliferative mechanisms on vascular cells, which may provide novel nonhormonal therapeutic targets for HPH.

Cited by 147 publications

References 76 publications

Oestradiol ameliorates monocrotaline pulmonary hypertensionviaNO, prostacyclin and endothelin-1 pathways

Oestradiol ameliorates monocrotaline pulmonary hypertensionviaNO, prostacyclin and endothelin-1 pathways

Pathobiology of pulmonary arterial hypertension: understanding the roads less travelled

Inhibiting oestrogen signalling in pulmonary arterial hypertension: sex, drugs and research

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