SOCS3 in retinal neurons and glial cells suppresses VEGF signaling to prevent pathological neovascular growth

Abstract

Accumulating evidence indicates that retinal neuroglia and neural cells contribute to neovascularization in proliferative retinopathy, but the controlling molecular interactions are not well known. We identified a mechanism by which neurons influence neovascularization through suppressor of cytokine signaling 3 (SOCS3) in neurons and glial cells. We found that Socs3 expression was increased in the retinal ganglion cell layer and inner nuclear layer after oxygen- induced retinopathy. Neuronal/glial Socs3 deficient mice with oxygen-induced retinopathy had significantly increased pathologic retinal neovascularization and reduced vaso-obliterated retinal areas, suggesting that loss of neuronal/glial SOCS3 increased both retinal vascular re-growth and pathological neovascularization. In response to oxygen-induced retinopathy, retinal vascular endothelial growth factor A (Vegfa) expression was higher in neuronal/glial Socs3 deficient mice than in than Socs3 flox/flox controls indicating that neuronal and glial Socs3 suppressed Vegfa during pathologic conditions. Lack of neuronal/glial SOCS3 resulted in greater phosphorylation and activation of STAT3, which led to increased expression of its gene target Vegfa, and increased endothelial cell proliferation. In summary, neuronal/glial SOCS3 suppresses endothelial cell activation through suppression of STAT3-mediated neuronal/glia VEGF secretion, resulting in less endothelial proliferation and angiogenesis. These results show that neuronal/glial SOCS3 regulates neurovascular interaction and pathologic retinal angiogenesis by titrating VEGF signaling.