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EDITORIAL FOCUS

Effect of chemical stabilizers of hypoxia-inducible factors on early lung development

¹CIHR Group in Lung Development, Hospital for Sick Children Research Institute, Departments of Pediatrics and Institute of Medical Sciences, University of Toronto, Toronto, Ontario, Canada; ²Department of Pediatric Surgery, Erasmus MC-Sophia, Rotterdam, The Netherlands; and ³Department of Obstetrics and Gynaecology, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada

Submitted 20 December 2006 ; accepted in final form 29 May 2007

Low oxygen stimulates pulmonary vascular development and airway branching and involves hypoxia-inducible factor (HIF). HIF is stable and initiates expression of angiogenic factors under hypoxia, whereas normoxia triggers hydroxylation of the HIF-1 subunit by prolyl hydroxylases (PHDs) and subsequent degradation. Herein, we investigated whether chemical stabilization of HIF-1 under normoxic (20% O₂) conditions would stimulate vascular growth and branching morphogenesis in early lung explants. Tie2-LacZ (endothelial LacZ marker) mice were used for visualization of the vasculature. Embryonic day 11.5 (E11.5) lung buds were dissected and cultured in 20% O₂ in the absence or presence of cobalt chloride (CoCl₂, a hypoxia mimetic), dimethyloxalylglycine (DMOG; a nonspecific inhibitor of PHDs), or desferrioxamine (DFO; an iron chelator). Vascularization was assessed by X-gal staining, and terminal buds were counted. The fine vascular network surrounding the developing lung buds seen in control explants disappeared in CoCl₂- and DFO-treated explants. Also, epithelial branching was reduced in the explants treated with CoCl₂ and DFO. In contrast, DMOG inhibited branching but stimulated vascularization. Both DFO and DMOG increased nuclear HIF-1 protein levels, whereas CoCl₂ had no effect. Since HIF-1 induces VEGF expression, the effect of SU-5416, a potent VEGF receptor (VEGFR) blocker, on early lung development was also investigated. Inhibition of VEGFR2 signaling in explants maintained under hypoxic (2% O₂) conditions completely abolished vascularization and slightly decreased epithelial branching. Taken together, the data suggest that DMOG stabilization of HIF-1 during early development leads to a hypervascular lung and that airway branching proceeds without the vasculature, albeit at a slower rate.

vascularization; lung development; vascular endothelial growth factor

This article has been cited by other articles:

				U. Berchner-Pfannschmidt, S. Frede, C. Wotzlaw, and J. Fandrey Imaging of the hypoxia-inducible factor pathway: insights into oxygen sensing Eur. Respir. J., July 1, 2008; 32(1): 210 - 217. [Abstract] [Full Text] [PDF]