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Pathological neoangiogenesis depends on oxidative stress regulation by ATM

Nature Medicine volume 18, pages 1208–1216 (2012)Cite this article

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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 p38α 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.

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Figure 1: Atm is activated specifically in newly formed pathological vessels in response to ROS accumulation.
Figure 2: Endothelial Atm is required for retinal pathological angiogenesis.
Figure 3: Atm promotes endothelial proliferation by suppressing ROS accumulation.
Figure 4: p38α acts downstream of Atm in endothelial cells.
Figure 5: Loss of Atm decreases tumor angiogenesis and enhances the antiangiogenic activity of Vegf blockade.
Figure 6: Atm deficiency does not affect the maintenance of healthy vessels in adult mice.

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Acknowledgements

We thank S. Kobayashi for outstanding technical support. We also thank F.W. Alt (Howard Hughes Medical Institute, Children's Hospital, Immune Disease Institute and Harvard Medical School) for providing Atmflox/flox mice, P.J. McKinnon (St. Jude Children's Research Hospital) for providing Atm−/− mice and H. Saya (Division of Gene Regulation, Keio University) for providing p53−/− mice. This work was supported by Grants-in-Aid for Specially Promoted Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan, by a research grant from Takeda Science Foundation, by the AstraZeneca Virtual Research Institute Research Grant and by the Keio Kanrinmaru Project.

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Authors and Affiliations

  1. Center for Integrated Medical Research, School of Medicine, Keio University, Tokyo, Japan

    Yuji Okuno & Yoshiaki Kubota

  2. Department of Cell Differentiation, The Sakaguchi Laboratory, School of Medicine, Keio University, Tokyo, Japan

    Ayako Nakamura-Ishizu & Toshio Suda

  3. Department of Cardiovascular Medicine, Osaka University, Graduate School of Medicine, Osaka, Japan

    Kinya Otsu

  4. Cardiovascular Division, King's College London, London, UK

    Kinya Otsu

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  1. Yuji Okuno
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Contributions

Y.O. and A.N.-I. performed experiments and analyzed data. T.S. interpreted results and assisted in manuscript preparation. K.O. provided experimental materials. Y.K. designed experiments, interpreted results and wrote the paper.

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Correspondence to Yoshiaki Kubota.

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Okuno, Y., Nakamura-Ishizu, A., Otsu, K. et al. Pathological neoangiogenesis depends on oxidative stress regulation by ATM. Nat Med 18, 1208–1216 (2012). https://doi.org/10.1038/nm.2846

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