Targeted deletion of Vegfa in adult mice induces vision loss

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

Research output: Contribution to journalArticle

181 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)4213-4217
Number of pages5
JournalJournal of Clinical Investigation
Volume122
Issue number11
DOIs
Publication statusPublished - 2012 Nov 1
Externally publishedYes

ASJC Scopus subject areas

  • Medicine(all)

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    Kurihara, T., Westenskow, P. D., Bravo, S., Aguilar, E., & Friedlander, M. (2012). Targeted deletion of Vegfa in adult mice induces vision loss. Journal of Clinical Investigation, 122(11), 4213-4217. https://doi.org/10.1172/JCI65157