Inhibition of endothelial cell apoptosis by netrin-1 during angiogenesis

Dev Cell. 2009 Apr;16(4):614-20. doi: 10.1016/j.devcel.2009.02.006.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects*
  • Apoptosis Regulatory Proteins / metabolism
  • Blood Vessels / abnormalities
  • Blood Vessels / drug effects
  • Calcium-Calmodulin-Dependent Protein Kinases / metabolism
  • Caspase Inhibitors
  • Death-Associated Protein Kinases
  • Embryo, Nonmammalian / cytology
  • Embryo, Nonmammalian / drug effects
  • Endothelial Cells / cytology*
  • Endothelial Cells / drug effects*
  • Endothelial Cells / enzymology
  • Enzyme Inhibitors / pharmacology
  • Gene Silencing / drug effects
  • Humans
  • In Vitro Techniques
  • Mice
  • Neovascularization, Physiologic / drug effects*
  • Nerve Growth Factors / pharmacology*
  • Netrin Receptors
  • Netrin-1
  • Phenotype
  • Protein Binding / drug effects
  • Rats
  • Receptors, Cell Surface / metabolism
  • Tumor Suppressor Proteins / pharmacology*
  • Zebrafish / embryology


  • Apoptosis Regulatory Proteins
  • Caspase Inhibitors
  • Enzyme Inhibitors
  • NTN1 protein, human
  • Nerve Growth Factors
  • Netrin Receptors
  • Ntn1 protein, mouse
  • Ntn1 protein, rat
  • Receptors, Cell Surface
  • Tumor Suppressor Proteins
  • Netrin-1
  • Death-Associated Protein Kinases
  • Calcium-Calmodulin-Dependent Protein Kinases