Sun, YeJu, MeihuaLin, ZhiqiangFredrick, T. W.Evans, L. P.Tian, KatherineSaba, N. J.Morss, P. C.Pu, WilliamChen, JingStahl, A.Joyal, JeanSmith, Lois2016-05-232015Sun, Y., M. Ju, Z. Lin, T. W. Fredrick, L. P. Evans, K. T. Tian, N. J. Saba, et al. 2015. “SOCS3 in Retinal Neurons and Glial Cells Suppresses VEGF Signaling to Prevent Pathological Neovascular Growth.” Science Signaling 8 (395) (September 22): ra94–ra94. doi:10.1126/scisignal.aaa8695.1945-0877http://nrs.harvard.edu/urn-3:HUL.InstRepos:27030122Accumulating 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.en-USSOCS3NeovascularizationVEGFNeurovascular interactionJournal Article2016-05-2310.1126/scisignal.aaa8695