TY - JOUR
T1 - Hypoxia-inducible factor-1 stimulates postnatal lung development but does not prevent o2-induced alveolar injury
AU - Tibboel, Jeroen
AU - Groenman, Freek A.
AU - Selvaratnam, Johanna
AU - Wang, Jinxia
AU - Tseu, Irene
AU - Huang, Zhen
AU - Caniggia, Isabella
AU - Luo, Daochun
AU - Tuyl, Minke Van
AU - Ackerley, Cameron
AU - Jongste, Johan C.De
AU - Tibboel, Dick
AU - Post, Martin
PY - 2015/1/1
Y1 - 2015/1/1
N2 - 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.
AB - 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.
KW - Alveologenesis
KW - Bronchopulmonary dysplasia
KW - Mice
KW - Vascular development
UR - http://www.scopus.com/inward/record.url?scp=84929659948&partnerID=8YFLogxK
U2 - https://doi.org/10.1165/rcmb.2014-0037OC
DO - https://doi.org/10.1165/rcmb.2014-0037OC
M3 - Article
C2 - 25180700
SN - 1044-1549
VL - 52
SP - 448
EP - 458
JO - American journal of respiratory cell and molecular biology
JF - American journal of respiratory cell and molecular biology
IS - 4
ER -