Gene expression profile of the murine ischemic retina and its response to Aflibercept (VEGF-Trap)

Abstract

Ischemic retinal dystrophies are leading causes of acquired vision loss. Although the dysregulated expression of the hypoxia-responsive VEGF-A is a major driver of ischemic retinopathies, implication of additional VEGF-family members in their pathogenesis has led to the development of multivalent anti-angiogenic tools. Designed as a decoy receptor for all ligands of VEGFR1 and VEGFR2, Aflibercept is a potent anti-angiogenic agent. Notwithstanding, the molecular mechanisms mediating Aflibercept’s efficacy remain only partially understood. Here, we used the oxygen-induced retinopathy (OIR) mouse as a model system of pathological retinal vascularization to investigate the transcriptional response of the murine retina to hypoxia and of the OIR retina to Aflibercept. While OIR severely impaired transcriptional changes normally ensuing during retinal development, analysis of gene expression patterns hinted at alterations in leukocyte recruitment during the recovery phase of the OIR protocol. Moreover, the levels of Angiopoietin-2, a major player in the progression of diabetic retinopathy, were elevated in OIR tissues and consistently downregulated by Aflibercept. Notably, GO term, KEGG pathway enrichment, and expression dynamics analyses revealed that, beyond regulating angiogenic processes, Aflibercept also modulated inflammation and supported synaptic transmission. Altogether, our findings delineate novel mechanisms potentially underlying Aflibercept’s efficacy against ischemic retinopathies.

Exploring Current Molecular Targets in the Treatment of Neovascular Age-Related Macular Degeneration toward the Perspective of Long-Term Agents

“…However, the expression of Ang-2 in the context of high VEGF levels contributes to angiogenesis, facilitating the responsiveness to VEGF [43]. Additionally, the inhibition of VEGF appeared to downregulate the levels of Ang-2, leading to normal protein levels in the vitreous and messenger RNA (mRNA) in the retina [44,45]. These findings were interpreted in light of clinical trial results from nesvacumab, a fully human IgG1 monoclonal antibody binding Ang-2 plus aflibercept that exhibited no significant benefits compared to aflibercept alone in treating both neovascular AMD and diabetic macular edema [46][47][48].…”

Aflibercept Suppression of Angiopoietin-2 in a Rabbit Retinal Vascular Hyperpermeability Model

“…1 Comparable findings are reported using an oxygen-induced retinopathy model in mice. 2 Rojo Arias et al 2 reported an increase of ANG2 expression in response to hypoxia, as well as a consistent down-regulation of ANG2 expression after treatment with aflibercept.…”