Neuronal influence in retinal ischemic disease. In ischemic retinopathies such as that of diabetes, regional microvascular decay yields zones of avascular neural tissue. (A) Angiogram of a human patient with DR. The red line delineates a zone of microcapillary loss with adjacent preretinal proliferation (white neovascular tuft). (Image courtesy of Dr Andreas Stahl, University Eye Hospital Freiburg.) (B) The schematic illustrates that in the avascular retina, hypoxic RGCs produce vasorepulsive semaphorins that repel nascent vessels into the vitreous and away from avascular zones of the retina. (C) Although ischemic astrocytes in the avascular retina produce VEGF via a HIF-2α–mediated mechanism, severely ischemic retinal ganglion neurons produce semaphorin 3A (D) and semaphorin 3E. (E) Astrocyte-derived VEGF stimulates vessel growth, whereas RGC-derived semaphorin 3A and 3E deviate vessels and thus impede reparative angiogenesis by repelling neovessels away from the avascular neural-retina toward the vitreous. (F) Hypoxia/ischemia is a major promoter of angiogenesis through mechanisms such as metabolite signaling and HIF-1α stabilization. When hypoxia persists and neurons are driven beyond a metabolic threshold, they revert to producing classic neuronal repulsive cues such as semaphorin 3A and 3E.