Fig. 1

VEGF and TNF signaling in retinal vascular disease. Increased expression of angiogenic and inflammatory factors (such as VEGF and TNFα) are associated with retinal vascular diseases. (1) The binding of VEGF to VEGFR2 in complex with α_vβ₃ integrin stimulates the autophosphorylation of VEGFR2 and the activation of downstream cellular processes. (2) These processes include the induction of migration and proliferation important for angiogenesis and the reorganization of diffuse actin into stress fibers and the internalization of cell–cell adhesion proteins that result in increased permeability. (3) VEGFR2 signaling also stimulates the release of Ang2 from Weibel-Palade bodies, which then competes with Ang1 to bind to Tie2 and reduce the associated signaling pathways related to vascular stability and anti-permeability. (4) With respect to inflammatory signaling, the binding of TNFα to the TNFR also stimulates the release of Ang2 from Weibel-Palade bodies (5) and reduces the activation of Tie2. This not only reduces the vessel stabilizing pathways mentioned above but also blocks the anti-inflammatory activity of the Tie2 receptor as well. (6) The activation of the TNFR pathway by TNFα also stimulates the relocation of NF-κB to the nucleus where it functions as a transcription factor to induce the expression of numerous inflammation-associated genes. (7) Among other functions, the initiation of inflammation stimulates increased permeability within blood vessels