Hypoxia-inducible factor-1 stimulates postnatal lung development but does not prevent o2-induced alveolar injury

Jeroen Tibboel, Freek A. Groenman, Johanna Selvaratnam, Jinxia Wang, Irene Tseu, Zhen Huang, Isabella Caniggia, Daochun Luo, Minke Van Tuyl, Cameron Ackerley, Johan C.De Jongste, Dick Tibboel, Martin Post

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This study investigated whether hypoxia-inducible factor (HIF)-1 influences postnatal vascularization and alveologenesis in mice and whether stable (constitutive-active) HIF could prevent hyperoxia-induced lung injury. We assessed postnatal vessel and alveolar formation in transgenic mice, expressing a stable, constitutive-active, HIF1a-subunit (HIF-1aDODD) in the distal lung epithelium. In addition,we compared lung function, histology, and morphometry of neonatal transgenic and wild-type mice subjected to hyperoxia. We found that postnatal lungs of HIF-1aDODDmice had a greater peripheral vessel density and displayed advanced alveolarization compared with control lungs. Stable HIF-1a expression was associated with increased postnatal expression of angiogenic factors, including vascular endothelial growth factor, angiopoietins 1 and 2, Tie2, and Ephrin B2 and B4. Hyperoxiaexposed neonatal HIF-1aDODD mice exhibited worse lung function but had similar histological and surfactant abnormalities compared with hyperoxia-exposed wild-type controls. In conclusion, expression of constitutive-active HIF-1a in the lung epithelium was associated with increased postnatal vessel growth via up-regulation of angiogenic factors. The increase in postnatal vasculature was accompanied by enhanced alveolar formation. However, stable HIF-1a expression in the distal lung did not prevent hyperoxia-induced lung injury in neonates but instead worsened lung function.

Original languageEnglish
Pages (from-to)448-458
Number of pages11
JournalAmerican journal of respiratory cell and molecular biology
Issue number4
Publication statusPublished - 1 Jan 2015


  • Alveologenesis
  • Bronchopulmonary dysplasia
  • Mice
  • Vascular development

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