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

Research output: Contribution to journalResearch articleContributedpeer-review

Contributors

Abstract

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.

Details

Original languageEnglish
Pages (from-to)390-412
Number of pages23
JournalJournal of neurochemistry
Volume153
Issue number3
Publication statusPublished - May 2020
Peer-reviewedYes

External IDs

Scopus 85074587460
ORCID /0000-0001-9467-7677/work/161888199
ORCID /0000-0001-9360-9736/work/164198475

Keywords

Sustainable Development Goals

Keywords

  • Animals, Animals, Newborn, Dopaminergic Neurons/drug effects, Female, Ischemia/drug therapy, Male, Mice, Microvessels/drug effects, Nerve Net/drug effects, Receptors, Vascular Endothelial Growth Factor/therapeutic use, Recombinant Fusion Proteins/pharmacology, Retinal Degeneration/drug therapy, Retinal Vessels/drug effects, Vasomotor System/drug effects