VEGF/VEGFR2 blockade does not cause retinal atrophy in AMD-relevant models
Da Long, Yogita Kanan, Jikui Shen, Sean F. Hackett, Yuanyuan Liu, Zibran Hafiz, Mahmood Khan, Lili Lu, Peter A. Campochiaro
Da Long, Yogita Kanan, Jikui Shen, Sean F. Hackett, Yuanyuan Liu, Zibran Hafiz, Mahmood Khan, Lili Lu, Peter A. Campochiaro
View: Text | PDF
Research Article Angiogenesis Ophthalmology

VEGF/VEGFR2 blockade does not cause retinal atrophy in AMD-relevant models

Abstract

Intraocular injections of VEGF-neutralizing proteins provide tremendous benefits in patients with choroidal neovascularization (NV) due to age-related macular degeneration (AMD), but during treatment some patients develop retinal atrophy. Suggesting that VEGF is a survival factor for retinal neurons, a clinical trial group attributed retinal atrophy to VEGF suppression and cautioned against frequent anti-VEGF injections. This recommendation may contribute to poor outcomes in clinical practice from insufficient treatment. Patients with type 3 choroidal NV have particularly high risk of retinal atrophy, an unexplained observation. Herein we show in mouse models that VEGF signaling does not contribute to photoreceptor survival and functioning: (a) neutralization of VEGFR2 strongly suppresses choroidal NV without compromising photoreceptor function or survival; (b) VEGF does not slow loss of photoreceptor function or death in mice with inherited retinal degeneration, and there is no exacerbation by VEGF suppression; and (c) mice with type 3 choroidal NV develop retinal atrophy due to oxidative damage with no contribution from VEGF suppression. Intraocular injections of VEGF-neutralizing proteins, a highly effective treatment in patients with neovascular AMD, should not be withheld or reduced due to concern that they may contribute to long-term visual loss from retinal atrophy.

Authors

Da Long, Yogita Kanan, Jikui Shen, Sean F. Hackett, Yuanyuan Liu, Zibran Hafiz, Mahmood Khan, Lili Lu, Peter A. Campochiaro

×

Figure 2

Effect of VEGF or VEGFR blockade on photoreceptor function and survival in rd10 mice with inherited retinal degeneration.

Options: View larger image (or click on image) Download as PowerPoint
Effect of VEGF or VEGFR blockade on photoreceptor function and survival ...
Rd10 mice were given an intravitreous injection of 100 ng of VEGF (n = 6) or PBS (n = 6) on P14, P21, and P28 or they were given subcutaneous injections of 5 μg of the VEGFR tyrosine kinase inhibitor SU4312 (n = 6) or vehicle (n = 6) every 5 days starting at P14. At P35, electroretinography showed that compared with eyes injected with vehicle control, those injected with VEGF had no significant differences in mean (±SEM) scotopic a-wave amplitudes (A), mean (±SEM) scotopic b-wave amplitudes (B), or mean (±SEM) photopic b-wave amplitudes (C). Compared with mice given subcutaneous vehicle injections, those given injections of SU4312 had no significant differences in mean (±SEM) scotopic a-wave amplitudes (D), mean (±SEM) scotopic b-wave amplitudes (E), or mean (±SEM) photopic b-wave amplitudes (F). At P35, mice were euthanized and retinal homogenates were immunoblotted for rhodopsin kinase (GRK1) and actin. The bands for GRK1 from vehicle-injected control eyes, VEGF-injected eyes, and eyes from mice treated with SU4312 appeared very similar (G). The mean (±SEM) ratio of GRK1/actin densitometry readings were not significantly different between VEGF (n = 3) or SU4312 (n = 3) and vehicle controls (n = 3) by ANOVA with Bonferroni’s correction for multiple comparisons (H).