title: Sex affects bone morphogenetic protein type II receptor signaling in pulmonary artery smooth muscle cells.
abstract: BACKGROUND
  Major pulmonary arterial hypertension (PAH) registries report a greater incidence of PAH in women; mutations in the bone morphogenic protein type II receptor (BMPR-II) occur in approximately 80% of patients with heritable PAH (hPAH).
  
  
  OBJECTIVE
  We addressed the hypothesis that women may be predisposed to PAH due to normally reduced basal BMPR-II signaling in human pulmonary artery smooth muscle cells (hPASMCs).
  
  
  METHODS
  We examined the BMPR-II signaling pathway in hPASMCs derived from men and women with no underlying cardiovascular disease (non-PAH hPASMCs). We also determined the development of pulmonary hypertension in male and female mice deficient in Smad1.
  
  
  RESULTS
  Platelet-derived growth factor, estrogen, and serotonin induced proliferation only in non-PAH female hPASMCs. Female non-PAH hPASMCs exhibited reduced messenger RNA and protein expression of BMPR-II, the signaling intermediary Smad1, and the downstream genes, inhibitors of DNA binding proteins, Id1 and Id3. Induction of phospho-Smad1/5/8 and Id protein by BMP4 was also reduced in female hPASMCs. BMP4 induced proliferation in female, but not male, hPASMCs. However, small interfering RNA silencing of Smad1 invoked proliferative responses to BMP4 in male hPASMCs. In male hPASMCs, estrogen decreased messenger RNA and protein expression of Id genes. The estrogen metabolite 4-hydroxyestradiol decreased phospho-Smad1/5/8 and Id expression in female hPASMCs while increasing these in males commensurate with a decreased proliferative effect in male hPASMCs. Female Smad1(+/-) mice developed pulmonary hypertension (reversed by ovariectomy).
  
  
  CONCLUSIONS
  We conclude that estrogen-driven suppression of BMPR-II signaling in non-PAH hPASMCs derived from women contributes to a pro-proliferative phenotype in hPASMCs that may predispose women to PAH.
authors.affiliation: 1 College of Medical and Veterinary Science, University of Glasgow, Glasgow, United Kingdom; and.
authors.forename: Kirsty M
authors.initials: KM
authors.lastname: Mair
authors.forename: Xu Dong
authors.initials: XD
authors.lastname: Yang
authors.forename: Lu
authors.initials: L
authors.lastname: Long
authors.forename: Kevin
authors.initials: K
authors.lastname: White
authors.forename: Emma
authors.initials: E
authors.lastname: Wallace
authors.forename: Marie-Ann
authors.initials: MA
authors.lastname: Ewart
authors.forename: Craig K
authors.initials: CK
authors.lastname: Docherty
authors.forename: Nicholas W
authors.initials: NW
authors.lastname: Morrell
authors.forename: Margaret R
authors.initials: MR
authors.lastname: MacLean
mesh_terms: D000818:Animals; D052006:Bone Morphogenetic Protein Receptors, Type II / Q000502:physiology*; D015536:Down-Regulation; D004967:Estrogens / Q000378:metabolism / Q000502:physiology; D005260:Female; D006801:Humans; D006976:Hypertension, Pulmonary; D008297:Male; D051379:Mice; D009131:Muscle, Smooth, Vascular / Q000166:cytology*; D011651:Pulmonary Artery / Q000166:cytology*; D012737:Sex Factors; D015398:Signal Transduction / Q000502:physiology
chemical_list: D004967:Estrogens; D052006:Bone Morphogenetic Protein Receptors, Type II
keywords: bone morphogenic protein type II; estrogen; proliferation; pulmonary hypertension; sex