Oestrogen receptor alpha in pulmonary hypertension

Audrey F. Wright, Marie-Ann Ewart, Kirsty Mair, Margaret Nilsen, Yvonne Dempsie, Lynn Loughlin, Margaret R. MacLean*

*Corresponding author for this work

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Abstract

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.
Original languageEnglish
Pages (from-to)206-216
Number of pages11
JournalCardiovascular Research
Volume106
Issue number2
Early online date12 Mar 2015
DOIs
Publication statusPublished - 1 May 2015

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Keywords

  • pulmonary arterial hypertension
  • oestrogen receptors
  • cardiology

Cite this

Wright, A. F., Ewart, M-A., Mair, K., Nilsen, M., Dempsie, Y., Loughlin, L., & MacLean, M. R. (2015). Oestrogen receptor alpha in pulmonary hypertension. Cardiovascular Research, 106(2), 206-216. https://doi.org/10.1093/cvr/cvv106