Mechanisms of Inflammation in Proliferative Vitreoretinopathy: From Bench to Bedside

Figure 1

Indirect activation of PDGFRα by non-PDGFs triggers the events leading to proliferative vitreoretinopathy (PVR). A retinal tear or detachment (a) creates an opening via which vitreal growth factors and cytokines interact with intraretinal cells and retinal pigment epithelial (RPE) cells. Vitreal VEGF-A competitively inhibits the binding of platelet-derived growth factors (PDGFs), including the predominant isoform isolated in the vitreous of patients with PVR, PDGF-C, to the receptor PDGFR-α (b). In doing so, VEGF-A prevents direct activation of PDGFRα by PDGFs. Direct activation of PDGFRα promotes rapid clearance of this receptor from the cell surface and subsequent intracellular degradation; this rapid receptor cycling interferes (b) with the ability of non-PDGFs to activate the PDGFRα through an indirect pathway as follows. Non-PDGFs, including basic fibroblast growth factor (bFGF), epidermal growth factor (EGF), insulin, and hepatocyte growth factor (HGF), activate their receptors, which results in an elevation of the level of intracellular reactive oxygen species (ROS), which leads to activation of Src family kinases (SFKs) that promote phosphorylation and activation of PDGFRα (c). This pathway of indirect activation results in persistent PDGFRα signaling and induces prolonged activation of phosphatidylinositol 3-kinase (PI3K)/Akt, which phosphorylates murine double minute (Mdm2), which then suppresses p53 levels (c). This promotes an environment of cell survival, proliferation, organization into a membrane, and subsequent membrane contraction, the processes intrinsic to PVR (d). Therefore, VEGF-A inhibits physiological, direct activation of PDGFRα by PDGFs and favors pathological, persistent, indirect activation of the receptor by non-PDGFs, triggering the events leading to PVR.