Sex-Dependent Influence of Endogenous Estrogen in Pulmonary Hypertension

Abstract

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.

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

“…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].…”

“…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].…”

“…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].…”

“…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][6][7][8]), implying that oestrogens can have biologically relevant effects throughout the body.…”

“…Based on the results of the pilot human trial [10] and recent experimental studies in a model of more severe PAH [6], a phase II study of anastrozole is currently underway. Could other strategies for inhibiting oestrogenic signalling be beneficial?…”