Oestrogen receptor alpha in pulmonary hypertension

Cardiovasc Res. 2015 May 1;106(2):206-16. doi: 10.1093/cvr/cvv106. Epub 2015 Mar 12.


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.

Keywords: BMPR2; Oestrogen; Oestrogen receptor alpha; Pulmonary hypertension; Serotonin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bone Morphogenetic Protein Receptors, Type II / genetics*
  • Bone Morphogenetic Protein Receptors, Type II / metabolism*
  • Cell Proliferation / physiology
  • Disease Models, Animal
  • Estrogen Receptor alpha / metabolism*
  • Humans
  • Hypertension, Pulmonary / genetics
  • Hypertension, Pulmonary / metabolism*
  • Hypertension, Pulmonary / pathology
  • Lung / metabolism
  • Mice
  • Myocytes, Smooth Muscle / metabolism
  • Serotonin Plasma Membrane Transport Proteins / metabolism*


  • Estrogen Receptor alpha
  • Serotonin Plasma Membrane Transport Proteins
  • Bmpr2 protein, mouse
  • Bone Morphogenetic Protein Receptors, Type II