title: Effects of intermittent hypoxia and hyperoxia on angiogenesis and lung development in newborn mice.
abstract: BACKGROUND
  Premature birth disrupts hypoxia driven microvascular development that directs alveolar and lung growth. Changes in oxygen exposure after birth can perturb the regulation of angiogenesis leading to bronchopulmonary dysplasia (BPD). We studied the effects of intermittent hypoxia or hyperoxia on HIF and angiogenic gene expression and lung development in newborn mice.
  
  
  METHODS
  Newborn litters were randomized within 12 h of birth to 12% O2 (4 h), 50% O2 (4 h) or 12% O2 (2 h)/50% O2 (2 h) followed by room air (RA) recovery for 20 h. Mice in RA were the control group. The mice were exposed to 6 such cycles (D1-D6) and sacrifice on D7. Whole lung mRNA was isolated and gene expression performed by qRT-PCR (HIF1α/2α/1β; PHD2, Ang1, Tie2, Vegf, VegfR1 & VegfR2) and analyzed by PCR array data analysis web portal. HIF-1α, prolyl hydroxylase-2 and VEGF protein were analyzed in whole lung by ELISA. Lung morphology was assessed by H&E sections and radial alveolar counts; cell proliferation by Ki67 immunostaining.
  
  
  RESULTS
  HIF-1α mRNA and VEGF protein were significantly downregulated in the 50% O2 group; VEGF mRNA and protein were significantly downregulated in the 12% O2-50% O2 group; Ang-1 and its receptor mRNA expression were downregulated in 12% O2 and 12% O2-50% O2 groups. 50% O2 (hyperoxia) and 12% O2-50% O2 (hypoxia-hyperoxia) groups demonstrated alveolar simplification by RAC and the same groups had decreased cell proliferation by Ki67 staining compared to RA and hypoxia (12% O2) groups.
  
  
  CONCLUSIONS
  Downregulation of HIF and angiogenic gene expression with associated changes in lung histology following intermittent hypoxia-hyperoxia is likely an important contributing factor in the development of BPD.
authors.forename: V D
authors.initials: VD
authors.lastname: Elberson
authors.forename: L C
authors.initials: LC
authors.lastname: Nielsen
authors.forename: H
authors.initials: H
authors.lastname: Wang
authors.forename: H S V
authors.initials: HS
authors.lastname: Kumar
mesh_terms: D042683:Angiopoietin-1 / Q000235:genetics; D000818:Animals; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator / Q000235:genetics; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics; D049109:Cell Proliferation; D015536:Down-Regulation; D015870:Gene Expression; D018496:Hyperoxia / Q000150:complications / Q000503:physiopathology*; D000860:Hypoxia / Q000150:complications / Q000503:physiopathology*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000032:analysis / Q000235:genetics; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases / Q000032:analysis / Q000235:genetics; D019394:Ki-67 Antigen / Q000032:analysis; D008168:Lung / Q000737:chemistry / Q000254:growth & development* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018919:Neovascularization, Physiologic / Q000235:genetics*; D012333:RNA, Messenger / Q000032:analysis*; D011897:Random Allocation; D042787:Receptor, TIE-2 / Q000235:genetics; D042461:Vascular Endothelial Growth Factor A / Q000032:analysis / Q000235:genetics; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000235:genetics; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D042683:Angiopoietin-1; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; D051792:Basic Helix-Loop-Helix Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases; D019394:Ki-67 Antigen; D012333:RNA, Messenger; D042787:Receptor, TIE-2; D042461:Vascular Endothelial Growth Factor A; D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2; D000099162:Endothelial PAS Domain-Containing Protein 1; C467628:Angpt1 protein, mouse; C497397:Arnt protein, mouse; C497443:Hif1a protein, mouse; C467480:vascular endothelial growth factor A, mouse; C490189:Egln1 protein, mouse; C000592875:Kdr protein, mouse; C079086:Tek protein, mouse
keywords: Oxygen; VEGF; hyperoxia; hypoxia; hypoxia inducible factor