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

¹ Institut National de la Santé et de la Recherche Médicale (INSERM) U833, F-75005 Paris, France; ² Collège de France, F-75005 Paris, France; ³ Service d’Hématologie Biologique A-AP-HP-Hôpital Européen Georges Pompidou, F-75015 Paris, France; ⁴ Sanofi-Aventis, F31036 Toulouse Cedex, France; ⁵ The Center for Transgene Technology and Gene Therapy, K.U. Leuven, Leuven B-3000, Belgium; ⁶ The Department of Transgene Technology and Gene Therapy, VIB, Leuven B-3000, Belgium; ⁷ INSERM U711, F-75013 Paris, France; ⁸ Université Pierre et Marie Curie, Faculté de Médecine Pitié Salpétrière, IFR 70, F-75005 Paris, France; ⁹ Genentech Inc., South San Francisco, California 94080, USA

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.

[Keywords: Vessel guidance; axon guidance molecules; tip cell; neovascularization; tumor angiogenesis]

Received April 23, 2007; revised version accepted August 3, 2007.

¹¹ Present addresses: Beijing Union Medical College and Chinese Academy of Medical Sciences, 100730 Beijing, China;

¹² School of Life Science, Xiamen University, 361005 Xiamen, China.

¹³ Corresponding author.

E-MAIL anne.eichmann@college-de-france.fr; FAX 33-1-44271691.

Supplemental material is available at http://www.genesdev.org.

Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.437807

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