Pathological neoangiogenesis depends on oxidative stress regulation by ATM.
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.
Center for Integrated Medical Research, School of Medicine, Keio University, Tokyo, Japan.
Yuji
Y
Okuno
Ayako
A
Nakamura-Ishizu
Kinya
K
Otsu
Toshio
T
Suda
Yoshiaki
Y
Kubota
D000111:Acetylcysteine / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D002478:Cells, Cultured / Q000187:drug effects / Q000378:metabolism; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D004730:Endothelium, Vascular / Q000503:physiopathology; D004789:Enzyme Activation; D005136:Eye Proteins / Q000502:physiology; D005260:Female; D006801:Humans; D006861:Hydrogen Peroxide / Q000037:antagonists & inhibitors / Q000633:toxicity; D007511:Ischemia / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D008546:Melanoma, Experimental / Q000098:blood supply; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009025:Morpholines / Q000494:pharmacology; D009389:Neovascularization, Pathologic / Q000503:physiopathology* / Q000517:prevention & control; D018384:Oxidative Stress / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D011753:Pyrones / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D015861:Retinal Neovascularization / Q000473:pathology / Q000503:physiopathology* / Q000517:prevention & control; D012171:Retinal Vessels / Q000187:drug effects / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects; D025521:Tumor Suppressor Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000502:physiology; D048051:p38 Mitogen-Activated Protein Kinases / Q000502:physiology
C495818:2-morpholin-4-yl-6-thianthren-1-yl-pyran-4-one; D000975:Antioxidants; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D005136:Eye Proteins; D009025:Morpholines; D011753:Pyrones; D017382:Reactive Oxygen Species; D025521:Tumor Suppressor Proteins; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D006861:Hydrogen Peroxide; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D017346:Protein Serine-Threonine Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D000111:Acetylcysteine