title: ANG-1 TIE-2 and BMPR signalling defects are not seen in the nitrofen model of pulmonary hypertension and congenital diaphragmatic hernia.
abstract: BACKGROUND
  Pulmonary hypertension (PH) is a lethal disease that is associated with characteristic histological abnormalities of the lung vasculature and defects of angiopoetin-1 (ANG-1), TIE-2 and bone morphogenetic protein receptor (BMPR)-related signalling. We hypothesized that if these signalling defects cause PH generically, they will be readily identifiable perinatally in congenital diaphragmatic hernia (CDH), where the typical pulmonary vascular changes are present before birth and are accompanied by PH after birth.
  
  
  METHODS
  CDH (predominantly left-sided, LCDH) was created in Sprague-Dawley rat pups by e9.5 maternal nitrofen administration. Left lungs from normal and LCDH pups were compared at fetal and postnatal time points for ANG-1, TIE-2, phosphorylated-TIE-2, phosphorylated-SMAD1/5/8 and phosphorylated-ERK1/2 by immunoprecipitation and Western blotting of lung protein extracts and by immunohistochemistry on lung sections.
  
  
  RESULTS
  In normal lung, pulmonary ANG-1 protein levels fall between fetal and postnatal life, while TIE-2 levels increase. Over the corresponding time period, LCDH lung retained normal expression of ANG-1, TIE-2, phosphorylated-TIE-2 and, downstream of BMPR, phosphorylated-SMAD1/5/8 and phosphorylated-p44/42.
  
  
  CONCLUSIONS
  In PH and CDH defects of ANG-1/TIE-2/BMPR-related signalling are not essential for the lethal vasculopathy.
authors.affiliation: Division of Child Health, Institute of Translational Medicine, The University of Liverpool, Liverpool, United Kingdom. harriet.corbett@alderhey.nhs.uk
authors.forename: Harriet Jane
authors.initials: HJ
authors.lastname: Corbett
authors.forename: Marilyn Gwen
authors.initials: MG
authors.lastname: Connell
authors.forename: David Garth
authors.initials: DG
authors.lastname: Fernig
authors.forename: Paul Damion
authors.initials: PD
authors.lastname: Losty
authors.forename: Edwin Chitran
authors.initials: EC
authors.lastname: Jesudason
mesh_terms: D042683:Angiopoietin-1 / Q000378:metabolism*; D000818:Animals; D000831:Animals, Newborn; D052004:Bone Morphogenetic Protein Receptors / Q000378:metabolism*; D004195:Disease Models, Animal; D005260:Female; D006548:Hernia, Diaphragmatic / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D065630:Hernias, Diaphragmatic, Congenital; D006973:Hypertension / Q000378:metabolism* / Q000473:pathology; D008168:Lung / Q000378:metabolism / Q000473:pathology; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D010647:Phenyl Ethers / Q000633:toxicity*; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D042787:Receptor, TIE-2 / Q000378:metabolism*; D015398:Signal Transduction; D051898:Smad1 Protein / Q000378:metabolism; D051902:Smad5 Protein / Q000378:metabolism; D051904:Smad8 Protein / Q000378:metabolism
chemical_list: D042683:Angiopoietin-1; D010647:Phenyl Ethers; D051898:Smad1 Protein; D051902:Smad5 Protein; D051904:Smad8 Protein; D042787:Receptor, TIE-2; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D052004:Bone Morphogenetic Protein Receptors; C007350:nitrofen