Inhibition of Endothelial Cell Apoptosis by Netrin-1 during Angiogenesis

• DOI: 10.1016/j.devcel.2009.02.006
• Publication Date: 2009-04-21T13:00:46Z
• Authors: Marie Castets; Marie-May Coissieux; Céline Delloye-Bo...; Laure Bernard; Jean-Guy Delcros; Agnès Bernet; Vincent Laudet; Patrick Mehlen
• Keywords: 570; Embryo, Nonmammalian; [SDV]Life Sciences [q-bio]; 610; Neovascularization, Physiologic; DEVBIO; Apoptosis; In Vitro Techniques; Mice; 03 medical and health sciences; BIOLOGIE CELLULAIRE; Animals; Humans; [INFO]Computer Science [cs]; Gene Silencing; Nerve Growth Factors; Enzyme Inhibitors; 0303 health sciences; ZEBRAFISH; Endothelial Cells; Netrin-1; Caspase Inhibitors; Death-Associated Protein Kinases; Phenotype; Calcium-Calmodulin-Dependent Protein Kinases; Blood Vessels; Apoptosis Regulatory Proteins; Netrin Receptors; Developmental Biology; Protein Binding

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.