title: The serotonin transporter, gender, and 17β oestradiol in the development of pulmonary arterial hypertension.
abstract: OBJECTIVE
  Idiopathic and familial forms of pulmonary arterial hypertension (PAH) predominantly affect females through an unknown mechanism. Activity of the serotonin transporter (SERT) may modulate the development of PAH, and mice overexpressing SERT (SERT+ mice) develop PAH and severe hypoxia-induced PAH. In the central nervous system, oestrogens influence activity of the serotonin system. Therefore, we examined the influence of gender on the development of PAH in SERT+ mice and how this is modulated by female hormones.
  
  
  RESULTS
  PAH was assessed via measurement of right ventricular systolic pressure (RVSP), pulmonary vascular remodelling (PVR), and right ventricular hypertrophy. Male SERT+ mice did not develop PAH. Female SERT+ mice demonstrated increased RVSP and PVR and this was abolished by ovariectomy. Following exposure to hypoxia, SERT+ mice exhibited severe PAH and this was also attenuated by ovariectomy. Chronic administration of 17β oestradiol re-established the PAH phenotype in ovariectomized, normoxic, and hypoxic SERT+ mice. 17β oestradiol also up-regulated tryptophan hydroxylase-1 (TPH1), 5-hydroytryptamine(1B) (5-HT(1B)) receptor, and SERT expression in human pulmonary arterial smooth muscle cells (hPASMCs). 17β oestradiol stimulated hPASMC proliferation and this was inhibited by both the TPH inhibitor para-chlorophenylalanine and the 5-HT(1B) receptor antagonist SB224289.
  
  
  CONCLUSIONS
  17β oestradiol is critical to the development of PAH and severe hypoxia-induced PAH in female SERT+ mice. In hPASMCs, 17β oestradiol-induced proliferation is dependant on de novo serotonin synthesis and stimulation of the 5-HT(1B) receptor. These interactions between the serotonin system and 17β oestradiol may contribute to the increased risk of PAH associated with female gender.
authors.affiliation: Research Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary and Life Sciences, West Medical Building, University of Glasgow G12 8QQ, UK.
authors.forename: Kevin
authors.initials: K
authors.lastname: White
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Dempsie
authors.forename: Margaret
authors.initials: M
authors.lastname: Nilsen
authors.forename: Audrey F
authors.initials: AF
authors.lastname: Wright
authors.forename: Lynn
authors.initials: L
authors.lastname: Loughlin
authors.forename: Margaret R
authors.initials: MR
authors.lastname: MacLean
mesh_terms: D000818:Animals; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D004958:Estradiol / Q000378:metabolism* / Q000494:pharmacology; D065627:Familial Primary Pulmonary Hypertension; D005260:Female; D006801:Humans; D006976:Hypertension, Pulmonary / Q000453:epidemiology / Q000378:metabolism / Q000503:physiopathology; D000860:Hypoxia / Q000453:epidemiology / Q000378:metabolism / Q000503:physiopathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008817:Mice, Mutant Strains; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects; D010052:Ovariectomy; D010641:Phenotype; D011651:Pulmonary Artery / Q000166:cytology / Q000187:drug effects; D044302:Receptor, Serotonin, 5-HT1B / Q000378:metabolism; D012307:Risk Factors; D012701:Serotonin / Q000378:metabolism; D050486:Serotonin Plasma Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism*; D017678:Sex Distribution
chemical_list: D044302:Receptor, Serotonin, 5-HT1B; C493230:SLC6A4 protein, human; D050486:Serotonin Plasma Membrane Transport Proteins; C493231:Slc6a4 protein, mouse; D012701:Serotonin; D004958:Estradiol