VEGFR2 deletion increases susceptibility to photoreceptor degeneration through glial-neuronal interaction.

Intraocular anti-VEGFA injections are frequently used to counteract neovascularization in diseases such as the neovascular form of age-related macular degeneration (AMD). However, in the clinical context, patients with atrophic (dry) and neovascular (wet) AMD in the same eye will receive anti-VEGFA injections, but there are reports that this severely promotes the development of atrophic areas in dry AMD. To study this, we used mice with a tamoxifen-dependent deletion of Vegfr2 in the eye (Vegfr2Δeye) and the light damage model to mimic certain aspects of dry AMD. We examined retinal morphology and function, the degree of photoreceptor degeneration, and alterations of the retinal proteome. While steady-state retinal morphology and function were not altered due to VEGF signaling deficiency, light-induced photoreceptor degeneration was drastically exacerbated in Vegfr2Δeye retinae, concomitant with attenuated activation of the AKT kinase pathway. Furthermore, using single nuclei RNA sequencing data, we showed that in humans, Vegfr2 is predominantly expressed in macroglial cells of healthy, dry- and wet AMD retinae. This suggests a VEGF-dependent neuroprotective crosstalk from macroglial cells to photoreceptors and poses promising therapeutic options to attenuate photoreceptor degeneration in humans. Yet, our data also indicate that anti-VEGF therapy should be carefully considered in the presence of neurodegenerative comorbidities.