title: Hypoxia-inducible factor-1 stimulates postnatal lung development but does not prevent O2-induced alveolar injury.
abstract: 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, HIF1α-subunit (HIF-1αΔODD) 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-1αΔODD mice had a greater peripheral vessel density and displayed advanced alveolarization compared with control lungs. Stable HIF-1α 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. Hyperoxia-exposed neonatal HIF-1αΔODD 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-1α 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-1α expression in the distal lung did not prevent hyperoxia-induced lung injury in neonates but instead worsened lung function.
authors.affiliation: 1 Department of Physiology and Experimental Medicine, Hospital for Sick Children, Toronto, Canada.
authors.forename: Jeroen
authors.initials: J
authors.lastname: Tibboel
authors.forename: Freek A
authors.initials: FA
authors.lastname: Groenman
authors.forename: Johanna
authors.initials: J
authors.lastname: Selvaratnam
authors.forename: Jinxia
authors.initials: J
authors.lastname: Wang
authors.forename: Irene
authors.initials: I
authors.lastname: Tseu
authors.forename: Zhen
authors.initials: Z
authors.lastname: Huang
authors.forename: Isabella
authors.initials: I
authors.lastname: Caniggia
authors.forename: Daochun
authors.initials: D
authors.lastname: Luo
authors.forename: Minke
authors.initials: M
authors.lastname: van Tuyl
authors.forename: Cameron
authors.initials: C
authors.lastname: Ackerley
authors.forename: Johan C
authors.initials: JC
authors.lastname: de Jongste
authors.forename: Dick
authors.initials: D
authors.lastname: Tibboel
authors.forename: Martin
authors.initials: M
authors.lastname: Post
mesh_terms: D000818:Animals; D057809:HEK293 Cells; D006801:Humans; D018496:Hyperoxia / Q000378:metabolism* / Q000473:pathology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000502:physiology*; D008168:Lung / Q000378:metabolism* / Q000473:pathology; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011650:Pulmonary Alveoli / Q000378:metabolism / Q000473:pathology*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse
keywords: alveologenesis; bronchopulmonary dysplasia; mice; vascular development