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Effects of hyperoxia on VEGF, its receptors, and HIF-2 in the newborn rat lung

Departments of ¹Physiology, ²Obstetrics and Gynaecology, and ³Pediatrics, Canadian Institutes of Health Research Group in Perinatal Health and Disease, The Perinatal Research Centre, The University of Alberta, Edmonton, Alberta, Canada T6G 2S2

Submitted 19 August 2002 ; accepted in final form 6 March 2003

Signaling through the hypoxia inducible factor (HIF)-VEGF-VEGF receptor system (VEGF signaling system) leads to angiogenesis and epithelial cell proliferation and is a key mechanism regulating alveolarization in lungs of newborn rats. Hyperoxia exposure (>95% O₂ days 4–14) arrests lung alveolarization and may do so through suppression of the VEGF signaling system. Lung tissue mRNA levels of HIF-2 and VEGF increased from days 4–14 in normoxic animals, but hyperoxia suppressed these increases. Levels of HIF-2 and VEGF mRNA were correlated in the air but not the O₂-treated group, suggesting that the low levels of HIF-2 observed at high O₂ concentrations are not stimulating VEGF expression. VEGF₁₆₄ protein levels increased with developmental age, and with hyperoxia to day 9, but continuing hyperoxia decreased levels by day 12. VEGFR1 and VEGFR2 mRNA expression also increased in air-exposed animals, and these, too, were significantly decreased by hyperoxia by day 9 and day 12, respectively. Receptor protein levels did not increase with development; however, O₂ did decrease protein to less than air values. Hyperoxic suppression of VEGF signaling from days 9–14 may be one mechanism by which alveolarization is arrested.

alveolarization; oxygen; septation

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