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Activation of the UNC5B receptor by Netrin-1 inhibits sprouting angiogenesis

2007; Cold Spring Harbor Laboratory Press; Volume: 21; Issue: 19 Linguagem: Inglês

10.1101/gad.437807

1549-5477

Bruno Larrivée, Catarina Freitas, Marc Trombe, Xiang Lv, Benjamin DeLafarge, Yuan Li, Karine Bouvrée, Christiane Bréant, R. Toro, Nicolas Bréchot, Stéphane Germain, Françoise Bono, Frédérique Dol, Filip Claes, Christian Fischer, Monica Autiero, Jean‐Léon Thomas, Peter Carmeliet, Marc Tessier‐Lavigne, Anne Eichmann,

Hippo pathway signaling and YAP/TAZ

Netrins are secreted molecules with roles in axonal growth and angiogenesis. The Netrin receptor UNC5B is required during embryonic development for vascular patterning, suggesting that it may also contribute to postnatal and pathological angiogenesis. Here we show that unc5b is down-regulated in quiescent adult vasculature, but re-expressed during sprouting angiogenesis in matrigel and tumor implants. Stimulation of UNC5B-expressing neovessels with an agonist (Netrin-1) inhibits sprouting angiogenesis. Genetic loss of function of unc5b reduces Netrin-1-mediated angiogenesis inhibition. Expression of UNC5B full-length receptor also triggers endothelial cell repulsion in response to Netrin-1 in vitro, whereas a truncated UNC5B lacking the intracellular signaling domain fails to induce repulsion. These data show that UNC5B activation inhibits sprouting angiogenesis, thus identifying UNC5B as a potential anti-angiogenic target.