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
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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

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Figure 5

Retinal atrophy in rho/VEGF mice with type 3 choroidal neovascularization is not increased by suppression of VEGF by aflibercept.

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Retinal atrophy in rho/VEGF mice with type 3 choroidal neovascularizatio...
(A) Fundus photographs (columns 1 and 2) of 2 representative eyes from untreated (control) and aflibercept-treated P35 rho/VEGF mice show numerous hypopigmented spots with the appearance of somewhat fewer in aflibercept-treated eyes. Frozen sections stained with Griffonia simplicifolia agglutinin (GSA, green) lectin alone (column 3) or with nuclei of retinal cells counterstained with Hoechst (blue, column 4) show less neovascularization (NV) in the subretinal space and in close proximity to the outer nuclear layer (arrows) in aflibercept-treated eyes more easily seen in high-magnification images of control (B) and aflibercept-treated (C) eyes. Image analysis with investigator masked with respect to treatment group showed no statistically significant difference (P = 0.0933 by Mann-Whitney U test) in mean (±SEM) ratio of atrophic area/retinal area in aflibercept-treated rho/VEGF mice compared with control rho/VEGF mice (D), but the aflibercept-treated mice had significantly less subretinal NV (E). *P < 0.01 by Mann-Whitney U test. ns, not significant.