Hypoxia-inducible transcription factors (HIF-1 and HIF-2) are central mediators of hypoxia-induced angiogenesis. HIF activity is induced during hypoxia through the inhibition of oxygen-dependent proteasomal degradation. Prolyl-4-hydroxylase (PHD) enzymes utilize molecular oxygen as a substrate to hydroxylate and target HIF for proteasomal degradation. Under hypoxia, HIF-1 and HIF-2 are stabilized and activate the expression of proangiogenic genes, including Angiopoietin 1 (ANG-1); Angiopoietin 2 (ANG-2); Plasminogen activator inhibitor-1 (PAI-1); platelet-derived growth factor-B (PDGF-B); and vascular endothelial growth factor (VEGF).
Economopoulou et al. have revealed an important role for H2AX in hypoxia-induced angiogenesis. H2AX activity can be induced under hypoxia through ATR- and ATM-dependent mechanisms. Under hypoxia, ATR phosphorylates H2AX in response to the accumulation of single-stranded DNA at stalled replication forks. Additionally, ATM phosphorylates H2AX in response to DSBs generated by ROS during reoxygenation. Economopoulou et al. demonstrate that H2AX is important for maintaining endothelial cell proliferation under hypoxic conditions.