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.
Pubmed ID: 26642851 RIS Download
Mesh terms: Aniline Compounds | Animals | Antigens, CD | Cadherins | Capillary Permeability | Cell Movement | Endothelial Cells | Gene Deletion | Gene Silencing | Human Umbilical Vein Endothelial Cells | Mice, Inbred C57BL | Mice, Knockout | Neutrophils | Phosphorylation | Phosphotyrosine | RNA, Small Interfering | Receptor, TIE-2 | Receptor-Like Protein Tyrosine Phosphatases, Class 3 | Recombinant Fusion Proteins | Sulfonic Acids | rap1 GTP-Binding Proteins
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