A Rac/Cdc42 exchange factor complex promotes formation of lateral filopodia and blood vessel lumen morphogenesis

Nat Commun. 2015 Jul 1:6:7286. doi: 10.1038/ncomms8286.

Abstract

During angiogenesis, Rho-GTPases influence endothelial cell migration and cell-cell adhesion; however it is not known whether they control formation of vessel lumens, which are essential for blood flow. Here, using an organotypic system that recapitulates distinct stages of VEGF-dependent angiogenesis, we show that lumen formation requires early cytoskeletal remodelling and lateral cell-cell contacts, mediated through the RAC1 guanine nucleotide exchange factor (GEF) DOCK4 (dedicator of cytokinesis 4). DOCK4 signalling is necessary for lateral filopodial protrusions and tubule remodelling prior to lumen formation, whereas proximal, tip filopodia persist in the absence of DOCK4. VEGF-dependent Rac activation via DOCK4 is necessary for CDC42 activation to signal filopodia formation and depends on the activation of RHOG through the RHOG GEF, SGEF. VEGF promotes interaction of DOCK4 with the CDC42 GEF DOCK9. These studies identify a novel Rho-family GTPase activation cascade for the formation of endothelial cell filopodial protrusions necessary for tubule remodelling, thereby influencing subsequent stages of lumen morphogenesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cytoskeleton / metabolism
  • GTPase-Activating Proteins / physiology*
  • Guanine Nucleotide Exchange Factors / metabolism
  • Human Umbilical Vein Endothelial Cells
  • Humans
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neovascularization, Pathologic*
  • Neovascularization, Physiologic*
  • Pseudopodia / physiology*
  • Vascular Endothelial Growth Factor A / metabolism
  • cdc42 GTP-Binding Protein / metabolism
  • rho GTP-Binding Proteins / metabolism

Substances

  • DOCK4 protein, human
  • DOCK9 protein, human
  • GTPase-Activating Proteins
  • Guanine Nucleotide Exchange Factors
  • Vascular Endothelial Growth Factor A
  • RHOG protein, human
  • cdc42 GTP-Binding Protein
  • rho GTP-Binding Proteins