Targeted deletion of Vegfa in adult mice induces vision loss
Toshihide Kurihara, … , Edith Aguilar, Martin Friedlander
Toshihide Kurihara, … , Edith Aguilar, Martin Friedlander
Published October 24, 2012
Citation Information: J Clin Invest. 2012;122(11):4213-4217. https://doi.org/10.1172/JCI65157.
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Brief Report

Targeted deletion of Vegfa in adult mice induces vision loss

Abstract

Current therapies directed at controlling vascular abnormalities in cancers and neovascular eye diseases target VEGF and can slow the progression of these diseases. While the critical role of VEGF in development has been well described, the function of locally synthesized VEGF in the adult eye is incompletely understood. Here, we show that conditionally knocking out Vegfa in adult mouse retinal pigmented epithelial (RPE) cells, which regulate retinal homeostasis, rapidly leads to vision loss and ablation of the choriocapillaris, the major blood supply for the outer retina and photoreceptor cells. This deletion also caused rapid dysfunction of cone photoreceptors, the cells responsible for fine visual acuity and color vision. Furthermore, Vegfa deletion showed significant downregulation of multiple angiogenic genes in both physiological and pathological states, whereas the deletion of the upstream regulatory transcriptional factors HIFs did not affect the physiological expressions of angiogenic genes. These results suggest that endogenous VEGF provides critical trophic support necessary for retinal function. Targeting factors upstream of VEGF, such as HIFs, may be therapeutically advantageous compared with more potent and selective VEGF antagonists, which may have more off-target inhibitory trophic effects.

Authors

Toshihide Kurihara, Peter D. Westenskow, Stephen Bravo, Edith Aguilar, Martin Friedlander

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Figure 1

Inducible Vegfa deletion in adult RPE cells promotes rapid choriocapillaris degeneration and vision loss.

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Inducible Vegfa deletion in adult RPE cells promotes rapid choriocapilla...
(A) Electron micrographs of control (upper panel, Vegfaf/f without Cre) and mutant (lower panels, Vegfaf/f with VMD2-Cre) murine retinas 3 days after Vegfa deletion in adult RPE. Right panels are enlargements of the boxed regions of the left panels. Note that Vegfa mutants lack choriocapillaris normally observed in controls (asterisks). (B) ERG of Vegfa mutant eyes shows loss of photopic and flicker signals. b-wave amplitudes from flash, or first peaks from flicker, ERG in photopic light-adapted conditions captured in Vegfa mutants are significantly attenuated compared with the same retina prior to Vegfa gene deletion (n = 4 for each time point). This dramatic attenuation is consistent with vision loss. (C) Immunohistochemical analyses for cone-opsin in Vegfa mutants and controls 7 days after induction. The absence of cone outer segments is apparent in the Vegfa mutants. #P < 0.01; 2-tailed Student’s t tests. Error bars indicate mean ± SD. Scale bars: 10 μm (A ); 20 μm (C). ONL, outer nuclear layer; OS, outer segments; CC,choriocapillaris.