Netrin-4 inhibits angiogenesis via binding to neogenin and recruitment of Unc5B

Netrins are secreted molecules with roles in axon guidance and angiogenesis. We identified Netrin-4 as a gene specifically overexpressed in VEGF-stimulated endothelial cells (EC) in vitro as well as in vivo. Knockdown of Netrin-4 expression in EC increased their ability to form tubular structures on...

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Veröffentlicht in:Proceedings of the National Academy of Sciences - PNAS 2008-08, Vol.105 (34), p.12491-12496
Hauptverfasser: Lejmi, Esma, Leconte, Laurence, Pédron-Mazoyer, Sandrine, Ropert, Stanislas, Raoul, William, Lavalette, Sophie, Bouras, Ilyes, Feron, Jean-Guillaume, Maitre-Boube, Martine, Assayag, Franck, Feumi, Charles, Alemany, Monica, Jie, Tan Xian, Merkulova, Tatyana, Poupon, Marie-France, Ruchoux, Marie-Magdeleine, Tobelem, Gérard, Sennlaub, Florian, Plouët, Jean
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Sprache:eng
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Zusammenfassung:Netrins are secreted molecules with roles in axon guidance and angiogenesis. We identified Netrin-4 as a gene specifically overexpressed in VEGF-stimulated endothelial cells (EC) in vitro as well as in vivo. Knockdown of Netrin-4 expression in EC increased their ability to form tubular structures on Matrigel. To identify which receptor is involved, we showed by quantitative RT-PCR that EC express three of the six Netrin-1 cognate receptors: neogenin, Unc5B, and Unc5C. In contrast to Netrin-1, Netrin-4 bound only to neogenin but not to Unc5B or Unc5C receptors. Neutralization of Netrin-4 binding to neogenin by blocking antibodies abolished the chemotactic effect of Netrin-4. Furthermore, the silencing of either neogenin or Unc5B abolished Netrin-4 inhibitory effect on EC migration, suggesting that both receptors are essential for its function in vitro. Coimmunoprecipitation experiments demonstrated that Netrin-4 increased the association between Unc5B and neogenin on VEGF- or FGF-2-stimulated EC. Finally, we showed that Netrin-4 significantly reduced pathological angiogenesis in Matrigel and laser-induced choroidal neovascularization models. Interestingly, Netrin-4, neogenin, and Unc5B receptor expression was up-regulated in choroidal neovessel EC after laser injury. Moreover, Netrin-4 overexpression delayed tumor angiogenesis in a model of s.c. xenograft. We propose that Netrin-4 acts as an antiangiogenic factor through binding to neogenin and recruitment of Unc5B.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.0804008105