Pharmacologic Uncoupling of Angiogenesis and Inflammation during Initiation of Pathological Corneal Neovascularization

Pathological neovascularization occurs when a balance of pro- and anti-angiogenic factors is disrupted, accompanied by an amplifying inflammatory cascade. However, the interdependence of these responses and the mechanism triggering the initial angiogenic switch have remained unclear. We present data from an epithelial debridement model of corneal neovascularization describing an initial 3-day period when a substantial component of neovascular growth occurs. Administration of selective inhibitors shows that this initial growth requires signaling through VEGFR-2 (vascular endothelial growth factor receptor-2), independent of the accompanying inflammatory response. Instead, increased VEGF production is found prominently in repair epithelial cells and is increased prior to recruitment of neutrophil/granulocytes and macrophage/monocytes. Consequently, early granulocyte and monocyte depletion has little effect on corneal neovascularization outgrowth. These data indicate that it is possible to pharmacologically uncouple these mechanisms during early injury-driven neovascularization in the cornea and suggest that initial tissue responses are coordinated by repair epithelial cells. The mechanism initiating pathological corneal neovascularization (CoNV) remains unclear. After injury, substantial CoNV occurs during an initial, VEGFR-2-dependent phase, prior to influence from inflammatory cells. Pathological CoNV can be pharmacologically uncoupled from inflammatory cell recruitment and may be coordinated by VEGF from repair epithelial cells. This work reveals a window in which angiogenesis and inflammation can be selectively targeted during injury repair.