Journal Article

VEGF is an autocrine/paracrine neuroprotective factor for injured retinal ganglion neurons

Ivkovic, Ivana, Sahel, José-Alain, Roubeix, Christophe, Brunel, Nadège, Matonti, Frédéric, Picaud, Serge, Forster, Valérie, Froger, Nicolas, Baudouin, Christophe

2020

Overview

Vascular endothelial growth factor-A (VEGF) is the angiogenic factor promoting the pathological neovascularization in age-related macular degeneration (AMD) or diabetic macular edema (DME). Evidences have suggested a neurotrophic and neuroprotective role of VEGF, albeit in retina, cellular mechanisms underlying the VEGF neuroprotection remain elusive. Using purified adult retinal ganglion cells (RGCs) in culture, we demonstrated here that VEGF is released by RGCs themselves to promote their own survival, while VEGF neutralization by specific antibodies or traps drastically reduced the RGC survival. These results indicate an autocrine VEGF neuroprotection on RGCs. In parallel, VEGF produced by mixed retinal cells or by mesenchymal stem cells exerted a paracrine neuroprotection on RGCs. Such neuroprotective effect was obtained using the recombinant VEGF-B, suggesting the involvement of VEGF-R1 pathway in VEGF-elicited RGC survival. Finally, glaucomatous patients injected with VEGF traps (ranibizumab or aflibercept) due to either AMD or DME comorbidity, showed a significant reduction of RGC axon fiber layer thickness, consistent with the plausible reduction of the VEGF autocrine stimulation of RGCs. Our results provide evidence of the autocrine neuroprotective function of VEGF on RGCs is crucially involved to preserve injured RGCs such as in glaucomatous patients.

• Publisher: Nature Publishing Group,Nature Publishing Group UK
• Subject: Age / Aged / Aged, 80 and over / Angiogenesis / Animals / Autocrine Communication - drug effects / Autocrine signalling / Cell culture / Cell Survival - drug effects / Cells, Cultured / Diabetes mellitus / Diabetic Retinopathy - complications / Diabetic Retinopathy - drug therapy / Edema / Female / Glaucoma / Glaucoma - drug therapy / Glaucoma - etiology / Glaucoma - pathology / Humans / Intravitreal Injections / Life Sciences / Macular degeneration / Macular Degeneration - complications / Macular Degeneration - drug therapy / Macular Edema - complications / Macular Edema - drug therapy / Male / Mesenchymal Stem Cells - metabolism / Mesenchyme / Middle Aged / Monoclonal antibodies / Neurons and Cognition / Neuroprotection / Paracrine Communication - drug effects / Paracrine signalling / Primary Cell Culture / Prospective Studies / Ranibizumab - administration & dosage / Rats / Receptors, Vascular Endothelial Growth Factor - administration & dosage / Recombinant Fusion Proteins - administration & dosage / Recombinant Proteins - genetics / Recombinant Proteins - metabolism / Retina / Retinal ganglion cells / Retinal Ganglion Cells - drug effects / Retinal Ganglion Cells - metabolism / Retinal Ganglion Cells - pathology / Stem cells / Traps / Vascular endothelial growth factor / Vascular Endothelial Growth Factor A - antagonists & inhibitors / Vascular Endothelial Growth Factor A - metabolism / Vascular Endothelial Growth Factor B - genetics / Vascular Endothelial Growth Factor B - metabolism / Vascular Endothelial Growth Factor Receptor-1 - antagonists & inhibitors / Vascular Endothelial Growth Factor Receptor-1 - metabolism / Vascular endothelial growth factor receptors / Vascularization