The vascular endothelial growth factor receptor 2 (VEGFR2) is the main receptor for angiogenesis and a key regulator of blood vessel homeostasis. Receptors regulate their signalling processes through the endocytic routes, and it has been assumed that VEGFR2 internalises solely through canonical clathrin-mediated endocytosis. Now (p. 4091), Savvas Christoforidis and colleagues report that clathrin-mediated endocytosis is the predominant internalisation route for VEGFR2 only in the absence of a ligand. Upon presence of the vascular endothelial growth factor A (VEGFA) ligand, the internalisation route of the receptor switches to macropinocytosis, with only minor contributions from the clathrin pathway. The addition of VEGFA induces membrane ruffling and macropinocytosis of VEGFR2, which is mediated by the small GTPase Cdc42. Inhibition of macropinocytosis prevents the phosphorylation of ERK1/2 and Akt, downstream signalling effectors of VEGFR2. Further, the authors show that blockage of macropinocytosis or Cdc42 depletion prevents VEGFR2-induced endothelial cell sprouting, migration and survival. In vivo, the inhibition of macropinocytosis prevents the VEGFA-dependent formation of new blood vessels in mice and corneal neovascularisation in rabbits. This study shows an unexpected role for macropinocytosis during ligand-dependent VEGFR2 internalisation in angiogenesis.

• © 2016. Published by The Company of Biologists Ltd