VEGF‐Trap is a potent modulator of vasoregenerative responses and protects dopaminergic amacrine network integrity in degenerative ischemic neovascular retinopathy

Retinal hypoxia triggers abnormal vessel growth and microvascular hyper‐permeability in ischemic retinopathies. Whereas vascular endothelial growth factor A (VEGF‐A) inhibitors significantly hinder disease progression, their benefits to retinal neurons remain poorly understood. Similar to humans, oxygen‐induced retinopathy (OIR) mice exhibit severe retinal microvascular malformations and profound neuronal dysfunction. OIR mice are thus a phenocopy of human retinopathy of prematurity, and a proxy for investigating advanced stages of proliferative diabetic retinopathy. Hence, the OIR model offers an excellent platform for assessing morpho‐functional responses of the ischemic retina to anti‐angiogenic therapies. Using this model, we investigated the retinal responses to VEGF‐Trap (Aflibercept), an anti‐angiogenic agent recognizing ligands of VEGF receptors 1 and 2 that possesses regulatory approval for the treatment of neovascular age‐related macular degeneration, macular edema secondary to retinal vein occlusion and diabetic macular edema. Our results indicate that Aflibercept not only reduces the severity of retinal microvascular aberrations but also significantly improves neuroretinal function. Aflibercept administration significantly enhanced light‐responsiveness, as revealed by electroretinographic examinations, and led to increased numbers of dopaminergic amacrine cells. Additionally, retinal transcriptional profiling revealed the concerted regulation of both angiogenic and neuronal targets, including transcripts encoding subunits of transmitter receptors relevant to amacrine cell function. Thus, Aflibercept represents a promising therapeutic alternative for the treatment of further progressive ischemic retinal neurovasculopathies beyond the set of disease conditions for which it has regulatory approval. Cover Image for this issue: doi: 10.1111/jnc.14743. Aflibercept is a widely utilized anti‐VEGF agent. Using the oxygen‐induced retinopathy (OIR) mouse model, which phenocopies human retinopathy of prematurity and mimics the advanced stages of proliferative diabetic retinopathy, we show that systemic Aflibercept administration not only reduces neovascularization and vaso‐obliteration in the OIR retina by promoting tip cell selection, but also protects dopaminergic amacrine cells against hypoxia, ultimately enhancing the light‐responsiveness of the visual system. Cover Image for this issue: doi: 10.1111/jnc.14743.