Comparative study of VEGF inhibitors in Oxygen Induced Retinopathy (OIR) mouse model: Vascular, non-vascular and functional implications

SUBIRADA CALDARONE PAULA; CROCCI D; RABINOVICH G; RIDANO MAGALI E; LUNA JD; VAGLIENTI MV; PAZ MC; BARCELONA PF; MARIA CECILIA SANCHEZ

Congreso; ARVO Annual Meeting; 2018

Purpose: During the past decade, vascular endothelial growth factor (VEGF) inhibitors have become standard-of-care treatment for neovascular retinopathies. However, clinical management of these diseases is still limited. Recently, it was demonstrated novel anti-angiogenic functions for aflibercept beyond its antagonism against VEGF family members. We hypothesized that aflibercept could be better than anti-VEGF therapy, improving not only vascular but also non-vascular alterations and retinal function. Methods: The oxygen-induced retinopathy (OIR) mouse model is an excellent platform to test drugs for retinopathy of prematurity or proliferative diabetic retinopathy. Briefly, C57BL/6 mice (OIR, N=27) were exposed to 75% O2 from postnatal day (P) 7 to P12, after which they were brought to room air for additional five (P17) or nine days (P26). Some OIR mice were intraocular administered at P12 with 1,25 μg of bevacizumab (Anti-VEGF) (N=9), 2 μg of aflibercept (N=9) or vehicle (N=9). At P17 and P26 mice were sacrificed. Some retinas were isolated to analyze Glutamine Synthase (GS), Glial Fibrillary Acidic Protein (GFAP) and total caspase 3 expression by Western blots. Vascular staining at P17 with GSA isolectin B4 conjugated to Alexa 488 was also performed. Finally, retinal function was analyzed by electroretinography (ERG). GraphPad Prism program was employed for statistical analysis according to the experimental data.Results: Aflibercept therapy reduced the vascular alterations observed in the OIR mice in a similar way to anti-VEGF treatments. The retinas of mice injected with anti-VEGF had lower levels of total caspase 3 than those injected with aflibercept. Furthermore, unlike that observed in mice injected with anti-VEGF, the alterations in protein expression of GFAP and GS observed in control OIR mice are reduced in mice injected with aflibercept. Finally, there were no improvements in ERG response of mice injected with aflibercept compared to those injected with anti-VEGF and OIR control mice.Conclusions: Aflibercept therapy showed vascular improvement in a similar way to anti-VEGF although it improved also non-vascular alterations in the OIR model. However, the functional retinal damage of OIR mice was not able to be reversed with either of these two treatments. These findings highlight the need for novel and combined therapies for neovascular retinopathies.