Pathological neoangiogenesis depends on oxidative stress regulation by ATM

Yuji Okuno, Ayako Nakamura-Ishizu, Kinya Otsu, Toshio Suda, Yoshiaki Kubota

Research output: Contribution to journalArticlepeer-review

100 Citations (Scopus)

Abstract

The ataxia telangiectasia mutated (ATM) kinase, a master regulator of the DNA damage response (DDR), acts as a barrier to cellular senescence and tumorigenesis. Aside from DDR signaling, ATM also functions in oxidative defense. Here we show that Atm in mice is activated specifically in immature vessels in response to the accumulation of reactive oxygen species (ROS). Global or endothelial-specific Atm deficiency in mice blocked pathological neoangiogenesis in the retina. This block resulted from increased amounts of ROS and excessive activation of the mitogen activated kinase p38Î ± rather than from defects in the canonical DDR pathway. Atm deficiency also lowered tumor angiogenesis and enhanced the antiangiogenic action of vascular endothelial growth factor (Vegf) blockade. These data suggest that pathological neoangiogenesis requires ATM-mediated oxidative defense and that agents that promote excessive ROS generation may have beneficial effects in the treatment of neovascular disease.

Original languageEnglish
Pages (from-to)1208-1216
Number of pages9
JournalNature medicine
Volume18
Issue number8
DOIs
Publication statusPublished - 2012 Aug

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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