VEGF/VEGFR2 blockade does not cause retinal atrophy in AMD-relevant models
Da Long, … , Lili Lu, Peter A. Campochiaro
Da Long, … , Lili Lu, Peter A. Campochiaro
Published May 17, 2018
Citation Information: JCI Insight. 2018;3(10):e120231. https://doi.org/10.1172/jci.insight.120231.
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Categories: 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 1

Inhibition of VEGFR2 suppresses choroidal neovascularization (NV) without photoreceptor damage.

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Inhibition of VEGFR2 suppresses choroidal neovascularization (NV) withou...
Brown Norway rats had fundus photography (A, top left) and optical coherence tomography (A, bottom left) through the posterior pole at baseline and then were given 3 intravitreous injections a week apart of 40 μg of a neutralizing antibody directed against VEGFR2 in one eye and control IgG in the fellow eye. One week after the third injection, repeat fundus photography (A, top right) and optical coherence tomography (A, bottom right) showed no change in appearance or thickness of the retina. Electroretinography showed that compared with control IgG-injected eyes, those injected with anti-VEGFR2 had no significant differences in mean scotopic a-wave amplitudes (B), mean scotopic b-wave amplitudes (C), or mean photopic b-wave amplitudes (D) at any of several flash intensities tested. Rats were euthanized and outer nuclear layer (ONL) thickness was measured at 6 locations in the 12:00 to 6:00 meridian passing through the optic nerve. There were no significant differences in mean ONL thickness at any of the 6 locations in anti-VEGFR2–injected eyes versus those injected with control IgG (E). Brown Norway rats had laser-induced rupture of Bruch’s membrane at 4 locations in one eye followed by an intraocular injection of 20 μg anti-VEGFR2 (n = 8), 20 μg of control IgG (n = 8), 40 μg of aflibercept (anti-VEGF, n = 6), or PBS (n = 6). After 14 days, rats were euthanized and choroidal flat-mounts were stained with FITC-labeled Griffonia simplicifolia agglutinin lectin. Representative images show small areas of choroidal NV in eyes that had been injected with anti-VEGFR2 or aflibercept (anti-VEGF) and large areas of choroidal NV in eyes that had been injected with control IgG or PBS (F). Image analysis showed that compared with eyes injected with control IgG, those injected with anti-VEGFR2 had a significant reduction in the mean (±SEM) area of choroidal NV, and compared with eyes injected with PBS, those injected with aflibercept (anti-VEGF) had a significant reduction in the mean (±SEM) area of choroidal NV (G). *P < 0.05, **P < 0.0001 by ANOVA with Bonferroni’s correction for multiple comparisons.