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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.

References

  1. Ferrara, N. VEGF-A: a critical regulator of blood vessel growth. Eur. Cytokine Netw. 20, 158–163 (2009).

    CAS  PubMed  Google Scholar 

  2. Carmeliet, P. & Jain, R.K. Molecular mechanisms and clinical applications of angiogenesis. Nature 473, 298–307 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Ratner, M. Genentech discloses safety concerns over Avastin. Nat. Biotechnol. 22, 1198 (2004).

    Article  CAS  PubMed  Google Scholar 

  4. Kamba, T. & McDonald, D.M. Mechanisms of adverse effects of anti-VEGF therapy for cancer. Br. J. Cancer 96, 1788–1795 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Bergers, G. & Hanahan, D. Modes of resistance to anti-angiogenic therapy. Nat. Rev. Cancer 8, 592–603 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Weis, S.M. & Cheresh, D.A. Tumor angiogenesis: molecular pathways and therapeutic targets. Nat. Med. 17, 1359–1370 (2011).

    Article  CAS  PubMed  Google Scholar 

  7. Jain, R.K. et al. Biomarkers of response and resistance to antiangiogenic therapy. Nat. Rev. Clin. Oncol. 6, 327–338 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Saharinen, P., Eklund, L., Pulkki, K., Bono, P. & Alitalo, K. VEGF and angiopoietin signaling in tumor angiogenesis and metastasis. Trends Mol. Med. 17, 347–362 (2011).

    Article  CAS  PubMed  Google Scholar 

  9. Sedelnikova, O.A., Pilch, D.R., Redon, C. & Bonner, W.M. Histone H2AX in DNA damage and repair. Cancer Biol. Ther. 2, 233–235 (2003).

    Article  CAS  PubMed  Google Scholar 

  10. Shiloh, Y. ATM and related protein kinases: safeguarding genome integrity. Nat. Rev. Cancer 3, 155–168 (2003).

    Article  CAS  PubMed  Google Scholar 

  11. Economopoulou, M. et al. Histone H2AX is integral to hypoxia-driven neovascularization. Nat. Med. 15, 553–558 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Zhan, H., Suzuki, T., Aizawa, K., Miyagawa, K. & Nagai, R. Ataxia telangiectasia mutated (ATM)-mediated DNA damage response in oxidative stress-induced vascular endothelial cell senescence. J. Biol. Chem. 285, 29662–29670 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Boder, E. & Sedgwick, R.P. Ataxia-telangiectasia; a familial syndrome of progressive cerebellar ataxia, oculocutaneous telangiectasia and frequent pulmonary infection. Pediatrics 21, 526–554 (1958).

    CAS  PubMed  Google Scholar 

  14. Raz-Prag, D. et al. A role for vascular deficiency in retinal pathology in a mouse model of ataxia-telangiectasia. Am. J. Pathol. 179, 1533–1541 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Bakkenist, C.J. & Kastan, M.B. DNA damage activates ATM through intermolecular autophosphorylation and dimer dissociation. Nature 421, 499–506 (2003).

    Article  CAS  PubMed  Google Scholar 

  16. Smith, L.E. et al. Oxygen-induced retinopathy in the mouse. Invest. Ophthalmol. Vis. Sci. 35, 101–111 (1994).

    CAS  PubMed  Google Scholar 

  17. Connor, K.M. et al. Quantification of oxygen-induced retinopathy in the mouse: a model of vessel loss, vessel regrowth and pathological angiogenesis. Nat. Protoc. 4, 1565–1573 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Jain, R.K. Molecular regulation of vessel maturation. Nat. Med. 9, 685–693 (2003).

    Article  CAS  PubMed  Google Scholar 

  19. Lange, C. et al. Kinetics of retinal vaso-obliteration and neovascularisation in the oxygen-induced retinopathy (OIR) mouse model. Graefes Arch. Clin. Exp. Ophthalmol. 247, 1205–1211 (2009).

    Article  CAS  PubMed  Google Scholar 

  20. Dorrell, M.I. et al. Antioxidant or neurotrophic factor treatment preserves function in a mouse model of neovascularization-associated oxidative stress. J. Clin. Invest. 119, 611–623 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Kubota, Y. et al. M-CSF inhibition selectively targets pathological angiogenesis and lymphangiogenesis. J. Exp. Med. 206, 1089–1102 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Fukushima, Y. et al. Sema3E-PlexinD1 signaling selectively suppresses disoriented angiogenesis in ischemic retinopathy in mice. J. Clin. Invest. 121, 1974–1985 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Clausen, B.E., Burkhardt, C., Reith, W., Renkawitz, R. & Förster, I. Conditional gene targeting in macrophages and granulocytes using LysMcre mice. Transgenic Res. 8, 265–277 (1999).

    Article  CAS  PubMed  Google Scholar 

  24. Marquardt, T. et al. Pax6 is required for the multipotent state of retinal progenitor cells. Cell 105, 43–55 (2001).

    Article  CAS  PubMed  Google Scholar 

  25. Lau, A. et al. Suppression of HIV-1 infection by a small molecule inhibitor of the ATM kinase. Nat. Cell Biol. 7, 493–500 (2005).

    Article  PubMed  Google Scholar 

  26. Sawamiphak, S. et al. Ephrin-B2 regulates VEGFR2 function in developmental and tumour angiogenesis. Nature 465, 487–491 (2010).

    Article  CAS  PubMed  Google Scholar 

  27. Ito, K. et al. Reactive oxygen species act through p38 MAPK to limit the lifespan of hematopoietic stem cells. Nat. Med. 12, 446–451 (2006).

    Article  CAS  PubMed  Google Scholar 

  28. Barlow, C. et al. Loss of the ataxia-telangiectasia gene product causes oxidative damage in target organs. Proc. Natl. Acad. Sci. USA 96, 9915–9919 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Barzilai, A., Rotman, G. & Shiloh, Y. ATM deficiency and oxidative stress: a new dimension of defective response to DNA damage. DNA Repair (Amst.) 1, 3–25 (2002).

    Article  CAS  Google Scholar 

  30. McKinnon, P.J. ATM and the molecular pathogenesis of ataxia telangiectasia. Annu. Rev. Pathol. 7, 303–321 (2012).

    Article  CAS  PubMed  Google Scholar 

  31. Trachootham, D., Alexandre, J. & Huang, P. Targeting cancer cells by ROS-mediated mechanisms: a radical therapeutic approach? Nat. Rev. Drug Discov. 8, 579–591 (2009).

    Article  CAS  PubMed  Google Scholar 

  32. Iwasa, H., Han, J. & Ishikawa, F. Mitogen-activated protein kinase p38 defines the common senescence-signalling pathway. Genes Cells 8, 131–144 (2003).

    Article  CAS  PubMed  Google Scholar 

  33. Tourian, L. Jr., Zhao, H. & Srikant, C.B. p38α, but not p38β, inhibits the phosphorylation and presence of c-FLIPS in DISC to potentiate Fas-mediated caspase-8 activation and type I apoptotic signaling. J. Cell Sci. 117, 6459–6471 (2004).

    Article  CAS  PubMed  Google Scholar 

  34. Hida, K. & Klagsbrun, M. A new perspective on tumor endothelial cells: unexpected chromosome and centrosome abnormalities. Cancer Res. 65, 2507–2510 (2005).

    Article  CAS  PubMed  Google Scholar 

  35. Wellen, K.E. & Thompson, C.B. Cellular metabolic stress: considering how cells respond to nutrient excess. Mol. Cell 40, 323–332 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Granger, D.N. & Korthuis, R.J. Physiologic mechanisms of postischemic tissue injury. Annu. Rev. Physiol. 57, 311–332 (1995).

    Article  CAS  PubMed  Google Scholar 

  37. Cosentino, C., Grieco, D. & Costanzo, V. ATM activates the pentose phosphate pathway promoting anti-oxidant defence and DNA repair. EMBO J. 30, 546–555 (2011).

    Article  CAS  PubMed  Google Scholar 

  38. Xia, C. et al. Reactive oxygen species regulate angiogenesis and tumor growth through vascular endothelial growth factor. Cancer Res. 67, 10823–10830 (2007).

    Article  CAS  PubMed  Google Scholar 

  39. Dong, A. et al. Oxidative stress promotes ocular neovascularization. J. Cell Physiol. 219, 544–552 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. West, X.Z. et al. Oxidative stress induces angiogenesis by activating TLR2 with novel endogenous ligands. Nature 467, 972–976 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Guo, Z., Kozlov, S., Lavin, M.F., Person, M.D. & Paull, T.T. ATM activation by oxidative stress. Science 330, 517–521 (2010).

    Article  CAS  PubMed  Google Scholar 

  42. Herzog, K.H., Chong, M.J., Kapsetaki, M., Morgan, J.I. & McKinnon, P.J. Requirement for Atm in ionizing radiation-induced cell death in the developing central nervous system. Science 280, 1089–1091 (1998).

    Article  CAS  PubMed  Google Scholar 

  43. Zhang, D. et al. Cre-loxP controlled periodic Aurora-A overexpression inducesmitotic abnormalities and hyperplasia in mammary glands of mouse models. Oncogene 23, 8720–8730 (2004).

    Article  CAS  PubMed  Google Scholar 

  44. Zha, S. et al. Ataxia telangiectasia-mutated protein and DNA-dependent protein kinase have complementary V(D)J recombination functions. Proc. Natl. Acad. Sci. USA 108, 2028–2033 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Nishida, K. et al. p38α mitogen-activated protein kinase plays a critical role in cardiomyocyte survival but not in cardiac hypertrophic growth in response to pressure overload. Mol. Cell. Biol. 24, 10611–10620 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Pan, H. et al. Molecular targeting of antiangiogenic factor 16K hPRL inhibits oxygen-induced retinopathy in mice. Invest. Ophthalmol. Vis. Sci. 45, 2413–2419 (2004).

    Article  PubMed  Google Scholar 

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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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