title: Endothelin-Bone morphogenetic protein type 2 receptor interaction induces pulmonary artery smooth muscle cell hyperplasia in pulmonary arterial hypertension.
abstract: BACKGROUND
  Endothelin receptor antagonists improve pulmonary arterial hypertension (PAH). Mutations in the bone morphogenetic protein (BMP) type 2 receptor (BMPR2) predispose to PAH. Here, we sought to determine whether there might exist interactions between these 2 signaling pathways and their effect on the acquisition of the altered phenotype of pulmonary artery smooth muscle cells (PA-SMCs) observed in PAH.
  
  
  METHODS
  Expression of BMPR2, of the BMP agonist BMP4, and of the BMP antagonists gremlin1 and gremlin2 was evaluated in lungs and in PA-SMCs from 6 PAH patients and 14 controls treated with endothelin-1. Endothelin-1 pre-treated PA-SMCs were assessed for proliferation, apoptosis, and downstream signaling activation of Smad1/5/8 and p38 mitogen-activated protein kinase (p38(MAPK)) after BMP2 treatment.
  
  
  RESULTS
  In PA-SMCs from PAH patients, expression of BMPR2 and BMP4 decreased, whereas expression of gremlin1 and gremlin2 increased compared with controls. Treatment of control PA-SMCs with endothelin-1 induced a dose-dependent increase in gremlin1 and gremlin2, whereas BMPR2 and BMP4 expression decreased, reaching similar levels as those observed in PAH cells. In control PA-SMCs, endothelin-1 pre-treatment reduced inhibitor of DNA binding 1 (Id1) expression and Smad1/5/8 activation induced by BMP2, whereas it enhanced p38(MAPK) activation. Moreover, BMP2 decreased serum-induced proliferation and increased the pro-apoptotic Bax/Bcl-2 ratio. These effects were attenuated by endothelin-1 pre-treatment. Endothelin-1 did not alter BMPR2 signaling in PA-SMCs from PAH patients.
  
  
  CONCLUSIONS
  Endothelin-1 downregulates canonical BMPR2 signaling. This is related to decreased BMPR2 and increased anti-BMP gremlin expression associated with increased activation of p38(MAPK) and results in PA-SMC proliferation.
authors.affiliation: Laboratory of Physiology and Physiopathology, Faculty of Medicine, Université Libre de Bruxelles, Brussels, Belgium.
authors.forename: Hidekazu
authors.initials: H
authors.lastname: Maruyama
authors.affiliation: Laboratory of Physiology and Physiopathology, Faculty of Medicine, Université Libre de Bruxelles, Brussels, Belgium.
authors.forename: Céline
authors.initials: C
authors.lastname: Dewachter
authors.affiliation: Laboratory of Physiology and Physiopathology, Faculty of Medicine, Université Libre de Bruxelles, Brussels, Belgium; Department of Thoracic Surgery, Erasmus University Hospital, Brussels, Belgium; Department of Cardio-Vascular and Thoracic Surgery and Lung Transplantation, Mont-Godinne University Hospital, Dinant, Belgium.
authors.forename: Asmae
authors.initials: A
authors.lastname: Belhaj
authors.affiliation: Laboratory of Physiology and Physiopathology, Faculty of Medicine, Université Libre de Bruxelles, Brussels, Belgium; Department of Thoracic Surgery, Erasmus University Hospital, Brussels, Belgium; Department of Cardio-Vascular and Thoracic Surgery and Lung Transplantation, Mont-Godinne University Hospital, Dinant, Belgium.
authors.forename: Benoit
authors.initials: B
authors.lastname: Rondelet
authors.affiliation: Cardiovascular Division, Department of Internal Medicine, Institute of Clinical Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan and the Departments of.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Sakai
authors.affiliation: Anatomopathology.
authors.forename: Myriam
authors.initials: M
authors.lastname: Remmelink
authors.affiliation: Cardiology, Erasmus University Hospital, Brussels, Belgium.
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Vachiery
authors.affiliation: Laboratory of Physiology and Physiopathology, Faculty of Medicine, Université Libre de Bruxelles, Brussels, Belgium.
authors.forename: Robert
authors.initials: R
authors.lastname: Naeije
authors.affiliation: Laboratory of Physiology and Physiopathology, Faculty of Medicine, Université Libre de Bruxelles, Brussels, Belgium. Electronic address: ldewacht@ulb.ac.be.
authors.forename: Laurence
authors.initials: L
authors.lastname: Dewachter
mesh_terms: D017209:Apoptosis; D052006:Bone Morphogenetic Protein Receptors, Type II / Q000235:genetics* / Q000378:metabolism; D049109:Cell Proliferation; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D006965:Hyperplasia; D006976:Hypertension, Pulmonary / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009131:Muscle, Smooth, Vascular / Q000378:metabolism* / Q000473:pathology; D009154:Mutation; D011651:Pulmonary Artery / Q000378:metabolism / Q000473:pathology*; D012313:RNA / Q000235:genetics*; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction
chemical_list: D012313:RNA; C498218:BMPR2 protein, human; D052006:Bone Morphogenetic Protein Receptors, Type II
keywords: BMPR2; Pulmonary arterial hypertension; endothelin; gremlin; proliferation; pulmonary artery smooth muscle cell