Sex-dependent influence of endogenous estrogen in pulmonary hypertension

Mair, K. M. et al. (2014) Sex-dependent influence of endogenous estrogen in pulmonary hypertension. American Journal of Respiratory and Critical Care Medicine, 190(4), pp. 456-467. (doi:10.1164/rccm.201403-0483OC) (PMID:24956156) (PMCID:PMC4214128)

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Abstract

Rationale: The incidence of pulmonary arterial hypertension (PAH) is greater in women suggesting estrogens may play a role in the disease pathogenesis. Experimentally, in males exogenously administered estrogen can protect against PH; however in models that display female susceptibility estrogens may play a causative role. Objectives: To clarify the influence of endogenous estrogen and gender 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 gender on pulmonary expression of aromatase in these models and in lungs from PAH patients. Results: Anastrozole attenuated PH in both models studied, but only in females. To verify this effect was due to reduced estrogenic activity we confirmed that in hypoxic mice inhibition of estrogen receptor alpha also has a therapeutic effect specifically in females. Female rodent lung displays increased aromatase and decreased BMPR2 and Id1 expression compared to male. Anastrozole treatment reversed the impaired BMPR2 pathway in females. Increased aromatase expression was also detected in female human pulmonary artery smooth muscle cells compared to 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.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:MacLean, Professor Margaret and Loughlin, Mrs Lynn and Nilsen, Mrs Margaret and Wright, Miss Audrey and Rowlands, Prof David and Mair, Dr Kirsty
Authors: Mair, K. M., Wright, A. F., Duggan, N., Rowlands, D. J., Hussey, M. J., Roberts, S., Fullerton, J., Nilsen, M., Loughlin, L., Thomas, M., and MacLean, M. R.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
Journal Name:American Journal of Respiratory and Critical Care Medicine
Publisher:American Thoracic Society
ISSN:1073-449X
ISSN (Online):1535-4970
Copyright Holders:Copyright © 2014 American Thoracic Society
First Published:First published in American Journal of Respiratory and Critical Care Medicine 190(4):456-467
Publisher Policy:Reproduced in accordance with the copyright policy of the publisher.

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
573731Gender and the development of pulmonary arterial hypertension: regulation of genes from mouse to manMargaret MacLeanBritish Heart Foundation (BHF)RG/11/7/28916RI CARDIOVASCULAR & MEDICAL SCIENCES
573733Gender and the development of pulmonary arterial hypertension: regulation of genes from mouse to manMargaret MacLeanBritish Heart Foundation (BHF)RG/11/7/28916RI CARDIOVASCULAR & MEDICAL SCIENCES