Interfering with VE-PTP stabilizes endothelial junctions in vivo via Tie-2 in the absence of VE-cadherin

J Exp Med. 2015 Dec 14;212(13):2267-87. doi: 10.1084/jem.20150718. Epub 2015 Dec 7.


Vascular endothelial (VE)-protein tyrosine phosphatase (PTP) associates with VE-cadherin, thereby supporting its adhesive activity and endothelial junction integrity. VE-PTP also associates with Tie-2, dampening the tyrosine kinase activity of this receptor that can support stabilization of endothelial junctions. Here, we have analyzed how interference with VE-PTP affects the stability of endothelial junctions in vivo. Blocking VE-PTP by antibodies, a specific pharmacological inhibitor (AKB-9778), and gene ablation counteracted vascular leak induction by inflammatory mediators. In addition, leukocyte transmigration through the endothelial barrier was attenuated. Interference with Tie-2 expression in vivo reversed junction-stabilizing effects of AKB-9778 into junction-destabilizing effects. Furthermore, lack of Tie-2 was sufficient to weaken the vessel barrier. Mechanistically, inhibition of VE-PTP stabilized endothelial junctions via Tie-2, which triggered activation of Rap1, which then caused the dissolution of radial stress fibers via Rac1 and suppression of nonmuscle myosin II. Remarkably, VE-cadherin gene ablation did not abolish the junction-stabilizing effect of the VE-PTP inhibitor. Collectively, we conclude that inhibition of VE-PTP stabilizes challenged endothelial junctions in vivo via Tie-2 by a VE-cadherin-independent mechanism. In the absence of Tie-2, however, VE-PTP inhibition destabilizes endothelial barrier integrity in agreement with the VE-cadherin-supportive effect of VE-PTP.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aniline Compounds / pharmacology
  • Animals
  • Antigens, CD / metabolism
  • Cadherins / deficiency*
  • Cadherins / metabolism
  • Capillary Permeability / drug effects
  • Cell Movement / drug effects
  • Endothelial Cells / drug effects
  • Endothelial Cells / metabolism*
  • Endothelial Cells / ultrastructure
  • Gene Deletion
  • Gene Silencing / drug effects
  • Human Umbilical Vein Endothelial Cells / drug effects
  • Human Umbilical Vein Endothelial Cells / metabolism
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neutrophils / cytology
  • Neutrophils / drug effects
  • Phosphorylation / drug effects
  • Phosphotyrosine / metabolism
  • RNA, Small Interfering / metabolism
  • Receptor, TIE-2 / metabolism*
  • Receptor-Like Protein Tyrosine Phosphatases, Class 3 / metabolism*
  • Recombinant Fusion Proteins / pharmacology
  • Sulfonic Acids / pharmacology
  • rap1 GTP-Binding Proteins / metabolism


  • AKB-9778
  • Aniline Compounds
  • Antigens, CD
  • COMP-Ang1 fusion protein
  • Cadherins
  • RNA, Small Interfering
  • Recombinant Fusion Proteins
  • Sulfonic Acids
  • cadherin 5
  • Phosphotyrosine
  • Receptor, TIE-2
  • Receptor-Like Protein Tyrosine Phosphatases, Class 3
  • rap1 GTP-Binding Proteins