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Oestrogen receptor alpha in pulmonary hypertension

AIMS: Pulmonary arterial hypertension (PAH) occurs more frequently in women with mutations in bone morphogenetic protein receptor type 2 (BMPR2) and dysfunctional BMPR2 signalling underpinning heritable PAH. We have previously shown that serotonin can uncover a pulmonary hypertensive phenotype in BM...

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Autores principales: Wright, Audrey F., Ewart, Marie-Ann, Mair, Kirsty, Nilsen, Margaret, Dempsie, Yvonne, Loughlin, Lynn, Maclean, Margaret R.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4615797/
https://www.ncbi.nlm.nih.gov/pubmed/25765937
http://dx.doi.org/10.1093/cvr/cvv106
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author Wright, Audrey F.
Ewart, Marie-Ann
Mair, Kirsty
Nilsen, Margaret
Dempsie, Yvonne
Loughlin, Lynn
Maclean, Margaret R.
author_facet Wright, Audrey F.
Ewart, Marie-Ann
Mair, Kirsty
Nilsen, Margaret
Dempsie, Yvonne
Loughlin, Lynn
Maclean, Margaret R.
author_sort Wright, Audrey F.
collection PubMed
description AIMS: Pulmonary arterial hypertension (PAH) occurs more frequently in women with mutations in bone morphogenetic protein receptor type 2 (BMPR2) and dysfunctional BMPR2 signalling underpinning heritable PAH. We have previously shown that serotonin can uncover a pulmonary hypertensive phenotype in BMPR2(+/−) mice and that oestrogen can increase serotinergic signalling in human pulmonary arterial smooth muscle cells (hPASMCs). Hence, here we wished to characterize the expression of oestrogen receptors (ERs) in male and female human pulmonary arteries and have examined the influence of oestrogen and serotonin on BMPR2 and ERα expression. METHODS AND RESULTS: By immunohistochemistry, we showed that ERα, ERβ, and G-protein-coupled receptors are expressed in human pulmonary arteries localizing mainly to the smooth muscle layer which also expresses the serotonin transporter (SERT). Protein expression of ERα protein was higher in female PAH patient hPASMCs compared with male and serotonin also increased the expression of ERα. 17β-estradiol induced proliferation of hPASMCs via ERα activation and this engaged mitogen-activated protein kinase and Akt signalling. Female mice over-expressing SERT (SERT(+) mice) develop PH and the ERα antagonist MPP attenuated the development of PH in normoxic and hypoxic female SERT(+) mice. The therapeutic effects of MPP were accompanied by increased expression of BMPR2 in mouse lung. CONCLUSION: ERα is highly expressed in female hPASMCs from PAH patients and mediates oestrogen-induced proliferation of hPASMCs via mitogen-activated protein kinase and Akt signalling. Serotonin can increase ERα expression in hPASMCs and antagonism of ERα reverses serotonin-dependent PH in the mouse and increases BMPR2 expression.
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spelling pubmed-46157972015-10-26 Oestrogen receptor alpha in pulmonary hypertension Wright, Audrey F. Ewart, Marie-Ann Mair, Kirsty Nilsen, Margaret Dempsie, Yvonne Loughlin, Lynn Maclean, Margaret R. Cardiovasc Res Original Articles AIMS: Pulmonary arterial hypertension (PAH) occurs more frequently in women with mutations in bone morphogenetic protein receptor type 2 (BMPR2) and dysfunctional BMPR2 signalling underpinning heritable PAH. We have previously shown that serotonin can uncover a pulmonary hypertensive phenotype in BMPR2(+/−) mice and that oestrogen can increase serotinergic signalling in human pulmonary arterial smooth muscle cells (hPASMCs). Hence, here we wished to characterize the expression of oestrogen receptors (ERs) in male and female human pulmonary arteries and have examined the influence of oestrogen and serotonin on BMPR2 and ERα expression. METHODS AND RESULTS: By immunohistochemistry, we showed that ERα, ERβ, and G-protein-coupled receptors are expressed in human pulmonary arteries localizing mainly to the smooth muscle layer which also expresses the serotonin transporter (SERT). Protein expression of ERα protein was higher in female PAH patient hPASMCs compared with male and serotonin also increased the expression of ERα. 17β-estradiol induced proliferation of hPASMCs via ERα activation and this engaged mitogen-activated protein kinase and Akt signalling. Female mice over-expressing SERT (SERT(+) mice) develop PH and the ERα antagonist MPP attenuated the development of PH in normoxic and hypoxic female SERT(+) mice. The therapeutic effects of MPP were accompanied by increased expression of BMPR2 in mouse lung. CONCLUSION: ERα is highly expressed in female hPASMCs from PAH patients and mediates oestrogen-induced proliferation of hPASMCs via mitogen-activated protein kinase and Akt signalling. Serotonin can increase ERα expression in hPASMCs and antagonism of ERα reverses serotonin-dependent PH in the mouse and increases BMPR2 expression. Oxford University Press 2015-05-01 2015-03-12 /pmc/articles/PMC4615797/ /pubmed/25765937 http://dx.doi.org/10.1093/cvr/cvv106 Text en © The Author 2015. Published by Oxford University Press on behalf of the European Society of Cardiology. http://creativecommons.org/licenses/by/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Original Articles
Wright, Audrey F.
Ewart, Marie-Ann
Mair, Kirsty
Nilsen, Margaret
Dempsie, Yvonne
Loughlin, Lynn
Maclean, Margaret R.
Oestrogen receptor alpha in pulmonary hypertension
title Oestrogen receptor alpha in pulmonary hypertension
title_full Oestrogen receptor alpha in pulmonary hypertension
title_fullStr Oestrogen receptor alpha in pulmonary hypertension
title_full_unstemmed Oestrogen receptor alpha in pulmonary hypertension
title_short Oestrogen receptor alpha in pulmonary hypertension
title_sort oestrogen receptor alpha in pulmonary hypertension
topic Original Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4615797/
https://www.ncbi.nlm.nih.gov/pubmed/25765937
http://dx.doi.org/10.1093/cvr/cvv106
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