Abstract
AimsPulmonary 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 resultsBy 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.ConclusionERα 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.
Highlights
The incidence of pulmonary arterial hypertension (PAH) is greater in females
ERa is highly expressed in female human pulmonary arterial smooth muscle cells (hPASMCs) from PAH patients and mediates oestrogen-induced proliferation of hPASMCs via mitogen-activated protein kinase and Akt signalling
Dysfunctional bone morphogenetic protein receptor 2 (BMPR2) signalling is recognized to play a pivotal role in the development of PAH and mutations in BMPR2 are responsible for 80% of heritable PAH (HPAH) cases.[3]
Summary
The incidence of pulmonary arterial hypertension (PAH) is greater in females. For example, the female-to-male ratio is currently reported in the REVEAL Registry as approximately 4.1:1 for idiopathic PAH (IPAH) and 3.8:1 for associated PAH (APAH).[1,2] Dysfunctional bone morphogenetic protein receptor 2 (BMPR2) signalling is recognized to play a pivotal role in the development of PAH and mutations in BMPR2 are responsible for 80% of heritable PAH (HPAH) cases.[3]Female gender is known to increase the penetrance of BMPR2 mutations in HPAH.[3]. The incidence of pulmonary arterial hypertension (PAH) is greater in females. The female-to-male ratio is currently reported in the REVEAL Registry as approximately 4.1:1 for idiopathic PAH (IPAH) and 3.8:1 for associated PAH (APAH).[1,2] Dysfunctional bone morphogenetic protein receptor 2 (BMPR2) signalling is recognized to play a pivotal role in the development of PAH and mutations in BMPR2 are responsible for 80% of heritable PAH (HPAH) cases.[3]. Female gender is known to increase the penetrance of BMPR2 mutations in HPAH.[3] Reasons for these gender differences remain unclear, there is converging evidence suggesting that sex hormones, in particular oestrogens, are a major risk factor in females with PAH and play a pivotal role in PAH pathogenesis. Physiological concentrations of oestrogen mediate proliferation of human PASMCs and an inhibitor of endogenous oestrogen synthesis can reverse the development of PH in female rodents.[5,6]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
