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Histone H2AX functions in hypoxia‐driven neovascularisation
Author(s) -
Chavakis Triantafyllos,
Celeste Arkady,
Orlova Valeria,
Nussenzweig Andre,
Economopoulou Matina
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.21.5.a14
Subject(s) - angiogenesis , hypoxia (environmental) , microbiology and biotechnology , retina , biology , endothelial stem cell , apoptosis , dna damage , cell growth , cancer research , chemistry , in vitro , dna , biochemistry , oxygen , organic chemistry , neuroscience
Hypoxia induces replication arrest in cells, nevertheless, endothelial cells actively proliferate in hypoxia‐induced angiogenesis. To understand this we studied the DNA damage response to hypoxia in endothelial cells. Hypoxia induced a rapid ATR‐dependent response (chk1 phosphorylation) in endothelial cells accompanied by replication stress associated foci that were positive for RPA and PCNA. Phosphorylated H2AX (γ‐H2AX) and 53BP1 also localized to the hypoxia‐induced foci. To functionally define this hypoxia‐induced response we performed siRNA‐mediated knockdown of H2AX. H2AX knockdown marginally affected growth factor stimulated endothelial cell proliferation under normoxia but it inhibited endothelial proliferation under hypoxia almost completely. In vivo γ‐H2AX was detected in newly formed retina vessels in mice that were subjected to the hypoxia‐induced retina neovascularisation model, as opposed to normoxic mice. Whereas physiologic vessel formation in the retina was unaffected by H2AX deficiency, H2AX‐/‐ mice displayed a 50% reduction in hypoxia‐induced retina neovascularisation, associated with decreased endothelial cell proliferation and increased apoptosis in the retina. Together, H2AX functions to help endothelial cells overcome the hypoxia induced replication arrest, thus identifying a novel crosstalk between the DNA repair response and hypoxia‐driven angiogenesis.