Histone H2AX is integral to hypoxia-driven neovascularization

Hypoxia-triggered neovascularization occurs in many types of disease. Endothelial cells must be able to cope with hypoxic stress, which in other cell types can induce a DNA repair response and inhibit replication. Matina Economopoulou et al . now show that hypoxia induces the generation of a hallmark of the DNA repair response, phosphorylated histone H2AX, in proliferating endothelial cells and that H2AX function is required for neovascularization under hypoxic or ischemic conditions in vivo pages 491–493 .. H2A histone family member X (H2AX, encoded by H2AFX ) and its C-terminal phosphorylation (γ-H2AX) participates in the DNA damage response and mediates DNA repair 1 , 2 , 3 , 4 , 5 , 6 . Hypoxia is a physiological stress that induces a replication-associated DNA damage response 7 . Moreover, hypoxia is the major driving force for neovascularization 8 , as the hypoxia-mediated induction of vascular growth factors triggers endothelial cell proliferation 8 . Here we studied the role of the hypoxia-induced DNA damage response in endothelial cell function and in hypoxia-driven neovascularization in vivo . Hypoxia induced replication-associated generation of γ-H2AX in endothelial cells in vitro and in mice. Both in cultured cells and in mice, endothelial cell proliferation under hypoxic conditions was reduced by H2AX deficiency. Whereas developmental angiogenesis was not affected in H2afx −/− mice, hypoxia-induced neovascularization during pathologic proliferative retinopathy, in response to hind limb ischemia or during tumor angiogenesis was substantially lower in H2afx −/− mice. Moreover, endothelial-specific H2afx deletion resulted in reduced hypoxia-driven retina neovascularization and tumor neovascularization. Our findings establish that H2AX, and hence activation of the DNA repair response, is needed for endothelial cells to maintain their proliferation under hypoxic conditions and is crucial for hypoxia-driven neovascularization.