ku-55933 and Retinal-Neovascularization

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.

Topics: Acetylcysteine; Animals; Antioxidants; Apoptosis; Ataxia Telangiectasia Mutated Proteins; Cell Cycle Proteins; Cells, Cultured; DNA Repair; DNA-Binding Proteins; Endothelium, Vascular; Enzyme Activation; Eye Proteins; Female; Humans; Hydrogen Peroxide; Ischemia; Lipid Peroxidation; Male; Melanoma, Experimental; Mice; Mice, Inbred C57BL; Mice, Knockout; Morpholines; Neovascularization, Pathologic; Oxidative Stress; p38 Mitogen-Activated Protein Kinases; Protein Serine-Threonine Kinases; Pyrones; Reactive Oxygen Species; Retinal Neovascularization; Retinal Vessels; Signal Transduction; Tumor Suppressor Proteins; Vascular Endothelial Growth Factor A