Fig. 2
From: The Tie2 signaling pathway in retinal vascular diseases: a novel therapeutic target in the eye
Effects of AXT107-treatment in retinal vascular disease. (1) AXT107 binds to αvβ3 integrins and dissociates them from VEGFR2. (2) The disruption of these interactions directly inhibits the autophosphorylation of VEGFR2 in the presence of VEGF and further reduces VEGFR2 responses by increasing the internalization and degradation of the receptor, overall reducing the angiogenesis responses and induction of vessel permeability (3). (4) AXT107 also binds to α5β1 integrin heterodimers, which associate with Tie2, and dissociates the subunits. (5) α5 integrin and Tie2 then relocate to the endothelial cell–cell junctions and form clusters that can be activated following the binding of either Ang1 or Ang2. (6) Active Tie2 clusters stimulate downstream pathways associated with improved endothelial cell survival and the reorganization of intracellular actin from stress fibers into cortical actin that is distributed around the edges of the cell to stabilize the vasculature. (7) Initial activation of TNFR by TNFα does not seem to be affected by AXT107 treatment, resulting in the release of Ang2 from Weibel-Palade bodies. The released Ang2 contributes to the activation of Tie2 clusters formed following AXT107 treatment. (8) Signaling by the phosphorylated Tie2 clusters prevent the degradation of IκBα molecules, retaining NF-κB within the cytoplasm and blocking the induction of inflammation and the associated effects on vessel permeability, thereby contributing to increased vessel stability