title: Drastic shift from positive to negative estrogen effect on bone morphogenetic protein signaling in pulmonary arterial endothelial cells under hypoxia.
abstract: BACKGROUND
  To investigate the possible role of sex hormones in the pathogenesis of pulmonary arterial hypertension (PAH), the effect of β-estradiol (E2) on bone morphogenetic protein (BMP) signaling, a key signaling pathway involved in PAH, was studied in human pulmonary arterial endothelial cells (HPAEC).
  
  
  RESULTS
  BMP signaling molecules, including BMP receptor, Smad1/5/8 and Id1, were studied in HPAEC under 1% O2 (hypoxia) and 21% O2 (normoxia) as well as the effect of hypoxia-inducible factor (HIF)-1α expression in the presence of E2 on BMP signaling. The effects of an estrogen receptor (ER) antagonist (ICI 182,780) and cycloheximide, and the interaction of ER with Smad or HIF-1α were also studied. In the presence of E2, BMP signaling was augmented under normoxia but suppressed under hypoxia. HIF-1α accumulation suppressed BMP signaling, whereas HIF-1α inhibition augmented signaling. These effects were cancelled by ICI 182,780. Moreover, binding between ER, HIF-1α and phosphorylated (p)-Smad1/5/8 proteins occurred only under hypoxia. On inhibition of de novo synthesis with cycloheximide, however, p-Smad1/5/8 expression was suppressed only under normoxia.
  
  
  CONCLUSIONS
  The effects of E2 on BMP signaling in HPAEC altered depending on O2 concentration and different mechanisms may be involved. BMP and sex hormones may play an important role in PAH development.
authors.affiliation: Department of Pediatrics, Osaka University Graduate School of Medicine, Suita, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Ichimori
authors.forename: Shigetoyo
authors.initials: S
authors.lastname: Kogaki
authors.forename: Kunihiko
authors.initials: K
authors.lastname: Takahashi
authors.forename: Hidekazu
authors.initials: H
authors.lastname: Ishida
authors.forename: Jun
authors.initials: J
authors.lastname: Narita
authors.forename: Nobutoshi
authors.initials: N
authors.lastname: Nawa
authors.forename: Hiroki
authors.initials: H
authors.lastname: Baden
authors.forename: Toshiki
authors.initials: T
authors.lastname: Uchikawa
authors.forename: Yoko
authors.initials: Y
authors.lastname: Okada
authors.forename: Keiichi
authors.initials: K
authors.lastname: Ozono
mesh_terms: D019485:Bone Morphogenetic Proteins / Q000494:pharmacology*; D015687:Cell Hypoxia / Q000187:drug effects; D002478:Cells, Cultured; D003513:Cycloheximide / Q000494:pharmacology; D042783:Endothelial Cells / Q000378:metabolism* / Q000473:pathology; D004958:Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology*; D004965:Estrogen Antagonists / Q000494:pharmacology; D004967:Estrogens / Q000494:pharmacology*; D000077267:Fulvestrant; D006801:Humans; D006976:Hypertension, Pulmonary / Q000401:mortality* / Q000473:pathology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology*; D011651:Pulmonary Artery / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects*; D051785:Smad Proteins / Q000378:metabolism
chemical_list: D019485:Bone Morphogenetic Proteins; D004965:Estrogen Antagonists; D004967:Estrogens; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D011500:Protein Synthesis Inhibitors; D051785:Smad Proteins; D000077267:Fulvestrant; D004958:Estradiol; D003513:Cycloheximide