Inhibition of endothelial cell apoptosis by netrin-1 during angiogenesis.
Netrin-1 was recently proposed to play an important role in embryonic and pathological angiogenesis. However, data reported led to the apparently contradictory conclusions that netrin-1 is either a pro- or an antiangiogenic factor. Here, we reconcile these opposing observations by demonstrating that netrin-1 acts as a survival factor for endothelial cells, blocking the proapoptotic effect of the dependence receptor UNC5B and its downstream death signaling effector, the serine/threonine kinase DAPK. The netrin-1 effect on blood vessel development is mimicked by caspase inhibitors in ex vivo assays, and the inhibition of caspase activity, the silencing of the UNC5B receptor, and the silencing of DAPK are each sufficient to rescue the vascular sprouting defects induced by netrin-1 silencing in zebrafish. Thus, the proapoptotic effect of unbound UNC5B and the survival effect of netrin-1 on endothelial cells finely tune the angiogenic process.
Castets
Marie
M
Apoptosis, Cancer, and Development Laboratory, Equipe labellisée La Ligue, CNRS UMR5238, Université de Lyon, Centre Léon Bérard, Lyon, France.
Coissieux
Marie-May
MM
Delloye-Bourgeois
Céline
C
Bernard
Laure
L
Delcros
Jean-Guy
JG
Bernet
Agnès
A
Laudet
Vincent
V
Mehlen
Patrick
P
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001808:Blood Vessels / Q000002:abnormalities / Q000187:drug effects; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D061945:Caspase Inhibitors; D064550:Death-Associated Protein Kinases; D004625:Embryo, Nonmammalian / Q000166:cytology / Q000187:drug effects; D042783:Endothelial Cells / Q000166:cytology* / Q000187:drug effects* / Q000201:enzymology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D020868:Gene Silencing / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D051379:Mice; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D009414:Nerve Growth Factors / Q000494:pharmacology*; D000075386:Netrin Receptors; D000075388:Netrin-1; D010641:Phenotype; D011485:Protein Binding / Q000187:drug effects; D051381:Rats; D011956:Receptors, Cell Surface / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000494:pharmacology*; D015027:Zebrafish / Q000196:embryology
D051017:Apoptosis Regulatory Proteins; D061945:Caspase Inhibitors; D004791:Enzyme Inhibitors; C000617351:NTN1 protein, human; D009414:Nerve Growth Factors; D000075386:Netrin Receptors; C000617353:Ntn1 protein, mouse; C000617354:Ntn1 protein, rat; D011956:Receptors, Cell Surface; D025521:Tumor Suppressor Proteins; D000075388:Netrin-1; D064550:Death-Associated Protein Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases