title: Oestrogen receptor alpha in pulmonary hypertension.
abstract: OBJECTIVE
  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.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: College of Medical, Veterinary, and Life Sciences, Research Institute of Cardiovascular and Medical Sciences, University of Glasgow, Room 448, West Medical Building/Wolfson Link Building, Glasgow G12 8QQ, UK.
authors.forename: Audrey F
authors.initials: AF
authors.lastname: Wright
authors.affiliation: College of Medical, Veterinary, and Life Sciences, Research Institute of Cardiovascular and Medical Sciences, University of Glasgow, Room 448, West Medical Building/Wolfson Link Building, Glasgow G12 8QQ, UK.
authors.forename: Marie-Ann
authors.initials: MA
authors.lastname: Ewart
authors.affiliation: College of Medical, Veterinary, and Life Sciences, Research Institute of Cardiovascular and Medical Sciences, University of Glasgow, Room 448, West Medical Building/Wolfson Link Building, Glasgow G12 8QQ, UK.
authors.forename: Kirsty
authors.initials: K
authors.lastname: Mair
authors.affiliation: College of Medical, Veterinary, and Life Sciences, Research Institute of Cardiovascular and Medical Sciences, University of Glasgow, Room 448, West Medical Building/Wolfson Link Building, Glasgow G12 8QQ, UK.
authors.forename: Margaret
authors.initials: M
authors.lastname: Nilsen
authors.affiliation: School of Health and Life Sciences, Glasgow Caledonian University, Glasgow G4 0BA.
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Dempsie
authors.affiliation: College of Medical, Veterinary, and Life Sciences, Research Institute of Cardiovascular and Medical Sciences, University of Glasgow, Room 448, West Medical Building/Wolfson Link Building, Glasgow G12 8QQ, UK.
authors.forename: Lynn
authors.initials: L
authors.lastname: Loughlin
authors.affiliation: College of Medical, Veterinary, and Life Sciences, Research Institute of Cardiovascular and Medical Sciences, University of Glasgow, Room 448, West Medical Building/Wolfson Link Building, Glasgow G12 8QQ, UK mandy.maclean@glasgow.ac.uk.
authors.forename: Margaret R
authors.initials: MR
authors.lastname: Maclean
mesh_terms: D000818:Animals; D052006:Bone Morphogenetic Protein Receptors, Type II / Q000235:genetics* / Q000378:metabolism*; D049109:Cell Proliferation / Q000502:physiology; D004195:Disease Models, Animal; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D006801:Humans; D006976:Hypertension, Pulmonary / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008168:Lung / Q000378:metabolism; D051379:Mice; D032389:Myocytes, Smooth Muscle / Q000378:metabolism; D050486:Serotonin Plasma Membrane Transport Proteins / Q000378:metabolism*
chemical_list: D047628:Estrogen Receptor alpha; D050486:Serotonin Plasma Membrane Transport Proteins; C498219:Bmpr2 protein, mouse; D052006:Bone Morphogenetic Protein Receptors, Type II
keywords: BMPR2; Oestrogen; Oestrogen receptor alpha; Pulmonary hypertension; Serotonin