Histone H2AX is integral to hypoxia-driven neovascularization

Matina Economopoulou, Harald F. Langer, Arkady Celeste, Valeria V. Orlova, Eun Young Choi, Mingchao Ma, Athanassios Vassilopoulos, Elsa Callen, Chuxia Deng, Craig H. Bassing, Manfred Boehm, Andre Nussenzweig, Triantafyllos Chavakis*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

96 Scopus citations

Abstract

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. 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 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.

Original languageEnglish (US)
Pages (from-to)553-558
Number of pages6
JournalNature Medicine
Volume15
Issue number5
DOIs
StatePublished - May 2009

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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