Activation of the UNC5B receptor by Netrin-1 inhibits sprouting angiogenesis.
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.
Larrivée
Bruno
B
Institut National de la Santé et de la Recherche Médicale U833, F-75005 Paris, France.
Freitas
Catarina
C
Trombe
Marc
M
Lv
Xiang
X
Delafarge
Benjamin
B
Yuan
Li
L
Bouvrée
Karine
K
Bréant
Christiane
C
Del Toro
Raquel
R
Bréchot
Nicolas
N
Germain
Stéphane
S
Bono
Françoise
F
Dol
Frédérique
F
Claes
Filip
F
Fischer
Christian
C
Autiero
Monica
M
Thomas
Jean-Léon
JL
Carmeliet
Peter
P
Tessier-Lavigne
Marc
M
Eichmann
Anne
A
D000818:Animals; D003094:Collagen / Q000378:metabolism; D004338:Drug Combinations; D004730:Endothelium, Vascular / Q000378:metabolism; D007797:Laminin / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains; D009389:Neovascularization, Pathologic / Q000378:metabolism*; D009414:Nerve Growth Factors / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D000075386:Netrin Receptors; D000075388:Netrin-1; D011509:Proteoglycans / Q000378:metabolism; D011554:Pseudopodia / Q000187:drug effects; D051381:Rats; D011956:Receptors, Cell Surface / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*
D004338:Drug Combinations; D007797:Laminin; D009414:Nerve Growth Factors; D000075386:Netrin Receptors; C000617353:Ntn1 protein, mouse; C000617354:Ntn1 protein, rat; D011509:Proteoglycans; D011956:Receptors, Cell Surface; D025521:Tumor Suppressor Proteins; C059485:matrigel; D000075388:Netrin-1; D003094:Collagen