Pathological neoangiogenesis depends on oxidative stress regulation by ATM

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

Research output: Contribution to journalArticle

88 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

Fingerprint

Ataxia Telangiectasia
Oxidative stress
DNA Damage
Reactive Oxygen Species
Oxidative Stress
DNA
Phosphotransferases
Cell Aging
Mitogens
Vascular Endothelial Growth Factor A
Retina
Tumors
Carcinogenesis
Chemical activation
Defects
Neoplasms

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Pathological neoangiogenesis depends on oxidative stress regulation by ATM. / Okuno, Yuji; Nakamura-Ishizu, Ayako; Otsu, Kinya; Suda, Toshio; Kubota, Yoshiaki.

In: Nature Medicine, Vol. 18, No. 8, 08.2012, p. 1208-1216.

Research output: Contribution to journalArticle

Okuno, Y, Nakamura-Ishizu, A, Otsu, K, Suda, T & Kubota, Y 2012, 'Pathological neoangiogenesis depends on oxidative stress regulation by ATM', Nature Medicine, vol. 18, no. 8, pp. 1208-1216. https://doi.org/10.1038/nm.2846
Okuno, Yuji ; Nakamura-Ishizu, Ayako ; Otsu, Kinya ; Suda, Toshio ; Kubota, Yoshiaki. / Pathological neoangiogenesis depends on oxidative stress regulation by ATM. In: Nature Medicine. 2012 ; Vol. 18, No. 8. pp. 1208-1216.
@article{3153142de65e4e4587843bcade96b6f8,
title = "Pathological neoangiogenesis depends on oxidative stress regulation by ATM",
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 p38{\^I} ± 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.",
author = "Yuji Okuno and Ayako Nakamura-Ishizu and Kinya Otsu and Toshio Suda and Yoshiaki Kubota",
year = "2012",
month = "8",
doi = "10.1038/nm.2846",
language = "English",
volume = "18",
pages = "1208--1216",
journal = "Nature Medicine",
issn = "1078-8956",
publisher = "Nature Publishing Group",
number = "8",

}

TY - JOUR

T1 - Pathological neoangiogenesis depends on oxidative stress regulation by ATM

AU - Okuno, Yuji

AU - Nakamura-Ishizu, Ayako

AU - Otsu, Kinya

AU - Suda, Toshio

AU - Kubota, Yoshiaki

PY - 2012/8

Y1 - 2012/8

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84864701748&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84864701748&partnerID=8YFLogxK

U2 - 10.1038/nm.2846

DO - 10.1038/nm.2846

M3 - Article

VL - 18

SP - 1208

EP - 1216

JO - Nature Medicine

JF - Nature Medicine

SN - 1078-8956

IS - 8

ER -