Histone H2AX is integral to hypoxia-driven neovascularization.
H2A histone family member X (H2AX, encoded by H2AFX) and its C-terminal phosphorylation (gamma-H2AX) participates in the DNA damage response and mediates DNA repair. Hypoxia is a physiological stress that induces a replication-associated DNA damage response. Moreover, hypoxia is the major driving force for neovascularization, as the hypoxia-mediated induction of vascular growth factors triggers endothelial cell proliferation. 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 gamma-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.
Matina
M
Economopoulou
Harald F
HF
Langer
Arkady
A
Celeste
Valeria V
VV
Orlova
Eun Young
EY
Choi
Mingchao
M
Ma
Athanassios
A
Vassilopoulos
Elsa
E
Callen
Chuxia
C
Deng
Craig H
CH
Bassing
Manfred
M
Boehm
Andre
A
Nussenzweig
Triantafyllos
T
Chavakis
D000818:Animals; D004249:DNA Damage; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology / Q000503:physiopathology*; D017353:Gene Deletion; D006614:Hindlimb; D006657:Histones / Q000172:deficiency* / Q000235:genetics*; D006801:Humans; D006918:Hydroxyurea / Q000494:pharmacology; D000860:Hypoxia / Q000235:genetics / Q000503:physiopathology; D007511:Ischemia / Q000235:genetics / Q000503:physiopathology; D051379:Mice; D018345:Mice, Knockout; D009389:Neovascularization, Pathologic / Q000235:genetics* / Q000517:prevention & control; D010766:Phosphorylation; D012171:Retinal Vessels / Q000503:physiopathology*; D014471:Umbilical Veins / Q000187:drug effects / Q000502:physiology / Q000503:physiopathology
D006657:Histones; D006918:Hydroxyurea; C468783:H2AX protein, human; C475961:gamma-H2AX protein, mouse