title: BMPR2 gene delivery reduces mutation-related PAH and counteracts TGF-β-mediated pulmonary cell signalling.
abstract: OBJECTIVE
  Idiopathic, familial and secondary pulmonary arterial hypertension (PAH) are associated with reduced bone morphogenetic protein receptor type 2 (BMPR2) expression, and in some contexts, TGF-β upregulation. Our aims were to assess BMPR2 gene therapy in a PAH mouse model and to assess the impact on TGF-β signalling.
  
  
  METHODS
  Using a targeted in vivo gene delivery approach, we assessed the impact of BMPR2 gene delivery in a transgenic mouse model in which PAH was first induced by doxycycline driven expression of a dominant negative BMPR2 mutant (R899X). We also assessed the impact of BMPR2 gene delivery on TGF-β-induced changes in cell signalling in human pulmonary vascular endothelial and smooth muscle cells.
  
  
  RESULTS
  In the mouse model, changes in TGF-β levels were not detected, but BMPR2 gene delivery reversed the increase in right ventricle systolic pressure (RVSP) and Fulton Index (FI), associated with a trend to increased pulmonary endothelial nitric oxide synthase (eNOS) gene expression. In vitro, BMPR2 gene transfer reduced TGF-β effects on Smad2, Smad1/5/8 and Erk1/2 phosphorylation in human pulmonary arterial smooth muscle cells (HPASMC). BMPR2 was also found to upregulate nitric oxide (NO) production in lung derived human microvascular endothelial cells (HMVEC-L).
  
  
  CONCLUSIONS
  This study provides further evidence that BMPR2 modulation may have therapeutic potential. See Editorial, page 406.
authors.affiliation: Lung Research Laboratory, Hanson Institute, Adelaide, South Australia, Australia.|Thoracic Medicine, Royal Adelaide Hospital, Adelaide, South Australia, Australia.
authors.forename: Feng
authors.initials: F
authors.lastname: Feng
authors.affiliation: Lung Research Laboratory, Hanson Institute, Adelaide, South Australia, Australia.|Thoracic Medicine, Royal Adelaide Hospital, Adelaide, South Australia, Australia.|Department of Medicine, University of Adelaide, Adelaide, South Australia, Australia.
authors.forename: Rebecca L
authors.initials: RL
authors.lastname: Harper
authors.affiliation: Lung Research Laboratory, Hanson Institute, Adelaide, South Australia, Australia.|Thoracic Medicine, Royal Adelaide Hospital, Adelaide, South Australia, Australia.|Department of Medicine, University of Adelaide, Adelaide, South Australia, Australia.
authors.forename: Paul N
authors.initials: PN
authors.lastname: Reynolds
mesh_terms: D000818:Animals; D015153:Blotting, Western; D052006:Bone Morphogenetic Protein Receptors, Type II / Q000235:genetics* / Q000378:metabolism; D002478:Cells, Cultured; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000378:metabolism; D018014:Gene Transfer Techniques; D006801:Humans; D006976:Hypertension, Pulmonary / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D011651:Pulmonary Artery / Q000503:physiopathology; D012313:RNA / Q000235:genetics*; D060888:Real-Time Polymerase Chain Reaction; D016212:Transforming Growth Factor beta / Q000235:genetics* / Q000378:metabolism
chemical_list: D016212:Transforming Growth Factor beta; D012313:RNA; C498219:Bmpr2 protein, mouse; D052006:Bone Morphogenetic Protein Receptors, Type II
keywords: genetics; molecular biology; nitric oxide; pulmonary circulation and pulmonary hypertension