Sex-dependent influence of endogenous estrogen in pulmonary hypertension

Kirsty M. Mair, Audrey F. Wright, Nicholas Duggan, David J. Rowlands, Martin J. Hussey, Sonia Roberts, Josephine Fullerton, Margaret Nilsen, Lynn Loughlin, Matthew Thomas, Margaret R. MacLean

Research output: Contribution to journalArticle

52 Citations (Scopus)

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 confi rming a role for endogenous estrogen in the disease pathogenesis in females and suggests aromatase inhibitors may have therapeutic potential.

Original languageEnglish
Pages (from-to)456-467
Number of pages12
JournalAmerican Journal of Respiratory and Critical Care Medicine
Volume190
Issue number4
DOIs
Publication statusPublished - 15 Aug 2014

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Pulmonary Hypertension
Estrogens
Aromatase Inhibitors
Aromatase
Bone Morphogenetic Protein Receptors
Bone Morphogenetic Protein 2
Therapeutic Uses
Lung
Pulmonary Artery
Estrogen Receptors
Smooth Muscle Myocytes
Rodentia
Therapeutics
Phenotype
anastrozole
Incidence

Keywords

  • estrogen
  • pulmonary hypertension
  • sex

Cite this

Mair, Kirsty M. ; Wright, Audrey F. ; Duggan, Nicholas ; Rowlands, David J. ; Hussey, Martin J. ; Roberts, Sonia ; Fullerton, Josephine ; Nilsen, Margaret ; Loughlin, Lynn ; Thomas, Matthew ; MacLean, Margaret R. / Sex-dependent influence of endogenous estrogen in pulmonary hypertension. In: American Journal of Respiratory and Critical Care Medicine. 2014 ; Vol. 190, No. 4. pp. 456-467.
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Mair, KM, Wright, AF, Duggan, N, Rowlands, DJ, Hussey, MJ, Roberts, S, Fullerton, J, Nilsen, M, Loughlin, L, Thomas, M & MacLean, MR 2014, 'Sex-dependent influence of endogenous estrogen in pulmonary hypertension', American Journal of Respiratory and Critical Care Medicine, vol. 190, no. 4, pp. 456-467. https://doi.org/10.1164/rccm.201403-0483OC

Sex-dependent influence of endogenous estrogen in pulmonary hypertension. / Mair, Kirsty M.; Wright, Audrey F.; Duggan, Nicholas; Rowlands, David J.; Hussey, Martin J.; Roberts, Sonia; Fullerton, Josephine; Nilsen, Margaret; Loughlin, Lynn; Thomas, Matthew; MacLean, Margaret R.

In: American Journal of Respiratory and Critical Care Medicine, Vol. 190, No. 4, 15.08.2014, p. 456-467.

Research output: Contribution to journalArticle

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T1 - Sex-dependent influence of endogenous estrogen in pulmonary hypertension

AU - Mair, Kirsty M.

AU - Wright, Audrey F.

AU - Duggan, Nicholas

AU - Rowlands, David J.

AU - Hussey, Martin J.

AU - Roberts, Sonia

AU - Fullerton, Josephine

AU - Nilsen, Margaret

AU - Loughlin, Lynn

AU - Thomas, Matthew

AU - MacLean, Margaret R.

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N2 - 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 confi rming a role for endogenous estrogen in the disease pathogenesis in females and suggests aromatase inhibitors may have therapeutic potential.

AB - 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 confi rming a role for endogenous estrogen in the disease pathogenesis in females and suggests aromatase inhibitors may have therapeutic potential.

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