Hypoxia promotes oxidative base modifications in the pulmonary artery endothelial cell VEGF gene

In accord with previous studies in other cell types, we found that acute hypoxic exposure promoted time-dependent dichlorofluorescein fluorescence in pulmonary artery endothelial cells

Valentina Grishko

2002

Scholarcy highlights

  • Hypoxia, a stimulus for angiogenesis and vascular remodeling, has been proposed to use reactive oxygen species as second messengers in signal transduction
  • The finding that hypoxia increases DCF fluorescence provides reasonable support for the concept that hypoxia promotes an oxidant stress in pulmonary artery endothelial cells
  • As a second and independent strategy to determine whether hypoxia causes an oxidant stress in PAECs, we searched for evidence of oxidative modifications in mitochondrial DNA and in the nuclear vascular endothelial cell growth factor gene
  • We suspected that mtDNA would be a target of hypoxia-generated free radicals because the mitochondrial complex III component of oxidative phosphorylation may be a source of hypoxia-induced reactive species production
  • That cobalt, unlike hypoxia, probably promotes free-radical generation via a nonmitochondrial pathway . mtDNA is far more sensitive to oxidant-mediated damage than is nuclear DNA, an observation recently extended to human vascular endothelial and smooth muscle cells and confirmed in PAECs by these experiments
  • Lesion maps for nucleotides prevalently damaged by hypoxia were constructed. “Prevalent damage” to a nucleotide was defined as a hypoxia-induced increase in hybridization intensity of at least 50% greater than the normoxic control
  • We examined the effects of hypoxia on the nuclear VEGF gene based on the suspicion that it would be protected despite the postulated damage to mtDNA
  • The surprising finding that nuclear DNA, including functionally significant sequences within he vascular endothelial cell growth factor promoter, is oxidatively modified in hypoxia raises new questions about the mechanism(s) by which reactive species generated in the context of physiologic and pathologic signaling govern cellular responses

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