The adaptor protein p66Shc is a positive regulator in the angiogenic response induced by hypoxic T cells.
Immune cells play an important role in the onset of angiogenesis. Here, we report that VEGF represents the major proangiogenic factor expressed by T cells exposed to hypoxia, a common feature of inflammation and tumor microenvironment. The supernatants of hypoxic T cells were highly angiogenic when delivered on the chick embryo CAM. The angiogenic response was abrogated by a neutralizing anti-VEGF antibody and mimicked by rVEGF. Interestingly, VEGF induction by hypoxia was up-regulated in Jurkat T cells overexpressing the adaptor protein p66Shc but not the inactive S36 p66Shc mutant, and it was abolished in p66Shc-/- mouse splenocytes. Accordingly, the angiogenic response induced by the supernatants from hypoxic p66Shc-/- splenocytes was reduced dramatically when compared with the wild-type controls. In conclusion, hypoxic T cells may contribute to the onset of angiogenesis through a novel VEGF-mediated mechanism, where p66Shc acts as a positive regulator.
Naldini
Antonella
A
Department of Physiology, University of Siena, Via Aldo Moro, 53100 Siena, Italy. naldini@unisi.it
Morena
Emilia
E
Pucci
Annalisa
A
Pellegrini
Michela
M
Baldari
Cosima T
CT
Pelicci
Pier Giuseppe
PG
Presta
Marco
M
Ribatti
Domenico
D
Carraro
Fabio
F
D000818:Animals; D015687:Cell Hypoxia; D002642:Chick Embryo; D017353:Gene Deletion; D005786:Gene Expression Regulation; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D019169:Jurkat Cells; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D051379:Mice; D018919:Neovascularization, Physiologic; D055765:Shc Signaling Adaptor Proteins / Q000378:metabolism*; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D013601:T-Lymphocytes / Q000166:cytology* / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism
D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C528024:SHC1 protein, human; D055765:Shc Signaling Adaptor Proteins; C528034:Shc1 protein, mouse; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D042461:Vascular Endothelial Growth Factor A