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 BMPR2(+/-) 2 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 ER alpha expression. Methods and results By immunohistochemistry, we showed that ER alpha, ER beta, 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 ER alpha protein was higher in female PAH patient hPASMCs compared with male and serotonin also increased the expression of ER alpha. 17 beta-estradiol induced proliferation of hPASMCs via ER alpha activation and this engaged mitogen-activated protein kinase and Akt signalling. Female mice over-expressing SERT (SERT+ mice) develop PH and the ER alpha 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 ER alpha 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 ER alpha expression in hPASMCs and antagonism of ER alpha reverses serotonin-dependent PH in the mouse and increases BMPR2 expression.