ATM promotes endothelial cell proliferation by suppressing reactive oxygen species.
Major finding: ATM promotes endothelial cell proliferation by suppressing reactive oxygen species.
Mechanism: ATM mediates angiogenesis through regulation of p38α, not the DNA damage response.
Impact: Specific targeting of ATM-mediated oxidative defense may be an effective antiangiogenic strategy.
One symptom of the cancer predisposition syndrome ataxia telangiectasia, caused by germline mutation in ataxia telangiectasia mutated (ATM), is decreased blood vessel stability. Okuno and colleagues thus evaluated the role of ATM in blood vessel formation. Activated ATM was specifically found in endothelial cells of pathologically expanding neovascular tufts in an ischemic retinopathy mouse model and in vessels of subcutaneously implanted tumors, but not in normal endothelial cells. Furthermore, neovascular tuft formation, but not normal blood vessel recovery, was ablated when ischemic retinopathy was induced in Atm-deficient or endothelial-specific Atm-knockout mice, and Atm-deficient adult mice had healthy blood vessels, indicating that ATM specifically mediates pathologic neoangiogenesis. ATM was activated in endothelial cells by elevated concentrations of reactive oxygen species (ROS) and was necessary for the expression of enzymes involved in ROS degradation. Interestingly, inhibition of ATM in endothelial cells increased ROS levels but did not cause DNA damage or affect proteins that act downstream of ATM in the DNA damage response. Instead, inhibition of endothelial ATM led to ROS-dependent activation of p38α, a kinase that induces growth arrest and apoptosis. Collectively, these results indicate that ATM might mediate a proangiogenic signaling pathway that could be targeted alone or in combination with VEGF blockade as an improved antiangiogenic therapy. Indeed, vessel density and growth of subcutaneous tumors were significantly reduced in endothelial-specific Atm-knockout mice compared with wild-type mice, and Atm deficiency synergized with VEGF blockade to inhibit angiogenesis and growth of implanted tumors. Although complete inhibition of ATM may not be feasible, given the role of ATM kinase activity in preventing DNA damage in many tissues, these findings suggest that specific targeting of ATM-mediated oxidative defense may be a well-tolerated, effective antiangiogenic strategy.