Complexities of oestradiol pharmacology in pulmonary arterial hypertension

Tofovic, Stevan P.; Jackson, Edwin K.

doi:10.1183/09031936.00164912

Cited by 6 publications

(7 citation statements)

References 8 publications

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“…Furthermore, as we aimed to investigate the specific potential of GPER independent of its activation by endogenous estrogens, the injection of MCT would low plasma E 2 levels by its gonadal actions (Tofovic and Jackson, 2013), reducing the physiologic stimulus of GPER and allowing to explore closely the effects of G1.…”

Section: Discussionmentioning

confidence: 99%

Activation of GPER ameliorates experimental pulmonary hypertension in male rats

Alencar

Montes

Montagnoli

et al. 2017

European Journal of Pharmaceutical Sciences

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Rationale Pulmonary hypertension (PH) is characterized by pulmonary vascular remodeling that leads to pulmonary congestion, uncompensated right-ventricle (RV) failure, and premature death. Preclinical studies have demonstrated that the G protein-coupled estrogen receptor (GPER) is cardioprotective in male rats and that its activation elicits vascular relaxation in rats of either sex. Objectives To study the effects of GPER on the cardiopulmonary system by the administration of its selective agonist G1 in male rats with monocrotaline (MCT)-induced PH. Methods Rats received a single intraperitoneal injection of MCT (60 mg/kg) for PH induction. Experimental groups were as follows: control, MCT + vehicle, and MCT + G1 (400 μg/kg/day subcutaneous). Animals (n = 5 per group) were treated with vehicle or G1 for 14 days after disease onset. Measurements and main results Activation of GPER attenuated exercise intolerance and reduced RV overload in PH rats. Rats with PH exhibited echocardiographic alterations, such as reduced pulmonary flow, RV hypertrophy, and left-ventricle dysfunction, by the end of protocol. G1 treatment reversed these PH-related abnormalities of cardiopulmonary function and structure, in part by promoting pulmonary endothelial nitric oxide synthesis, Ca2+ handling regulation and reduction of inflammation in cardiomyocytes, and a decrease of collagen deposition by acting in pulmonary and cardiac fibroblasts. Conclusions G1 was effective to reverse PH-induced RV dysfunction and exercise intolerance in male rats, a finding that have important implications for ongoing clinical evaluation of new cardioprotective and vasodilator drugs for the treatment of the disease.

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Section: Discussionmentioning

confidence: 99%

Activation of GPER ameliorates experimental pulmonary hypertension in male rats

Alencar

Montes

Montagnoli

et al. 2017

European Journal of Pharmaceutical Sciences

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“…These valuable studies examined the influence of estrogen administered to males where estrogen levels In addition, these studies use intact males, hence the presence of high endogenous testosterone combined with high circulating estrogen levels (because of the exogenously added estradiol) is not a state that would normally occur physiologically and may influence interpretation of results. In the instance of monocrotaline-induced PH the beneficial effects of estrogen may be caused by the fact that monocrotaline is a toxin reported to cause gonadal toxicity and reduce estrogen levels (16). In our experimental design we wished to compare males and females and address a different question: "what is the role of endogenous estrogen and is it different in intact males and females?…”

Section: Discussionmentioning

confidence: 99%

Sex-Dependent Influence of Endogenous Estrogen in Pulmonary Hypertension

Mair

Wright

Duggan

et al. 2014

Am J Respir Crit Care Med

124

185

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Rationale: The incidence of pulmonary arterial hypertension is greater in women, suggesting estrogens may play a role in the disease pathogenesis. Experimentally, in males, exogenously administered estrogen can protect against pulmonary hypertension (PH). However, in models that display female susceptibility, estrogens may play a causative role.Objectives: To clarify the influence of endogenous estrogen and sex in PH and assess the therapeutic potential of a clinically available aromatase inhibitor. Methods:We interrogated the effect of reduced endogenous estrogen in males and females using the aromatase inhibitor, anastrozole, in two models of PH: the hypoxic mouse and Sugen 5416/hypoxic rat. We also determined the effects of sex on pulmonary expression of aromatase in these models and in lungs from patients with pulmonary arterial hypertension.Measurements and Main Results: Anastrozole attenuated PH in both models studied, but only in females. To verify this effect was caused by reduced estrogenic activity we confirmed that in hypoxic mice inhibition of estrogen receptor a also has a therapeutic effect specifically in females. Female rodent lung displays increased aromatase and decreased bone morphogenetic protein receptor 2 and Id1 expression compared with male. Anastrozole treatment reversed the impaired bone morphogenetic protein receptor 2 pathway in females. Increased aromatase expression was also detected in female human pulmonary artery smooth muscle cells compared with male.Conclusions: The unique phenotype of female pulmonary arteries facilitates the therapeutic effects of anastrozole in experimental PH confirming a role for endogenous estrogen in the disease pathogenesis in females and suggests aromatase inhibitors may have therapeutic potential.Keywords: pulmonary hypertension; estrogen; sex At a Glance CommentaryScientific Knowledge on the Subject: Females develop pulmonary arterial hypertension (PAH) more frequently than males. The role of estrogen in this female susceptibility is poorly understood.What This Study Adds to the Field: Our research shows that inhibition of endogenous estrogen synthesis using an aromatase inhibitor or inhibition of estrogen receptor a has therapeutic effects and restores bone morphogenetic protein receptor 2 expression in female but not male models of PAH. These findings suggest estrogen plays a pathogenic role in the pathology of PAH specifically in females.

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“…[10,12,14,113] The apparent contradictions posed by the effects of female gender and estrogens in experimental PH versus human PAH may be explained by the complexity of E2 metabolism and limitations of the experimental models used. [14,114] Estrogen metabolites and the vasculature…”

Section: -Methoxyestradiol (2-me) Treatment Does Not Prevent Bmpr2-rmentioning

confidence: 99%

“…This may have significant ramifications for the overall effects of estrogens in experimental PH, and the overall effects of gender and E2 in experimental PH may depend on the model system used. [14,114] Therefore, it was suggested [129] that the effects of estrogens and their metabolites should be studied in a model that more closely mimics vascular (endothelial) alterations seen in human PAH, i.e., rat model of angioproliferative PH induced by administration of VEGFR2 antagonist SU5416 and exposure to hypoxia (Sugen [Su5416] plus hypoxia [SuHx rats]). [135] Opposite to the gender effects in hypoxia-and MCT-induced PAH, in this model of experimental PH, female gender does not protect against PH.…”

Section: -Methoxyestradiol (2-me) Treatment Does Not Prevent Bmpr2-rmentioning

confidence: 99%

Gender, Sex Hormones and Pulmonary Hypertension

et al. 2013

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Most subtypes of pulmonary arterial hypertension (PAH) are characterized by a greater susceptibility to disease among females, although females with PAH appear to live longer after diagnosis. While this “estrogen paradoxȍ of enhanced female survival despite increased female susceptibility remains a mystery, recent progress has begun to shed light upon the interplay of sex hormones, the pathogenesis of pulmonary hypertension, and the right ventricular response to stress. For example, emerging data in humans and experimental models suggest that estrogens or differential sex hormone metabolism may modify disease risk among susceptible subjects, and that estrogens may interact with additional local factors such as serotonin to enhance the potentially damaging chronic effects of estrogens on the pulmonary vasculature. Regardless, it remains unclear why not all estrogenic compounds behave equally, nor why estrogens appear to be protective in certain settings but detrimental in others. The contribution of androgens and other compounds, such as dehydroepiandrosterone, to pathogenesis and possibly treatment must be considered as well. In this review, we will discuss the recent understandings on how estrogens, estrogen metabolism, dehydroepiandrosterone, and additional susceptibility factors may all contribute to the pathogenesis or potentially to the treatment of pulmonary hypertension, by evaluating current human, cell-based, and experimental model data.

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Complexities of oestradiol pharmacology in pulmonary arterial hypertension

Cited by 6 publications

References 8 publications

Activation of GPER ameliorates experimental pulmonary hypertension in male rats

Activation of GPER ameliorates experimental pulmonary hypertension in male rats

Sex-Dependent Influence of Endogenous Estrogen in Pulmonary Hypertension

Gender, Sex Hormones and Pulmonary Hypertension

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