Purchase this article with an account.
Weiquan Zhu, Dallas Shujing Shi, Jacob Winter, Bianca Rich; Inhibiting VEGF Signaling by Targeting Receptor Trafficking in Diabetic Retinopathy. Invest. Ophthalmol. Vis. Sci. 2016;57(12):3207.
Download citation file:
© ARVO (1962-2015); The Authors (2016-present)
Vascular Endothelial Growth Factor (VEGF) is important for biological development and adult homeostasis, but also in disease. Pathogenic VEGF signaling has been successfully attenuated therapeutically by attacking both ligand and receptor. Our efforts to characterize the downstream components of VEGF signaling have identified VEGF receptor trafficking as another potential therapeutic disease target.
We use in vitro assays to elucidate the relationship between VEGF receptor activation and receptor trafficking. STZ-induced diabetic retinopathy models have been used to conform the cellular mechanism and efficacy of a smal molecul inhibitor.
In vitro assays elucidate a VEGFR2-ARNO axis that activates ARF6 to stimulate receptor internalization and a VEGFR2-GEP100-ARF6 axis that prevents VEGFR2 degradation through co-receptor binding. Here, we show that targeted inhibition of membrane trafficking significantly attenuates VEGF signaling, showed by decreased phosphorylation of VEGFR2 and its downstream effectors. Interestingly, we find this mechanism appears to extend beyond VEGFR2, as ARF6 is required for receptor activation of other RTKs such as EGFR. In diabetic retinopathy, hyperactive VEGF signaling causes blindness by destabilizing the retinal vasculature. In a mouse model of diabetic retinopathy, conditional knockout of Arf6 using endothelial-specific or whole body Cre drivers decreased retinal permeability. Furthermore, we demonstrate the efficacy of a small molecule inhibitor of ARF6 in treating diabetic retinopathy in mice and rats.
This study identifies ARF6 as a key component in RTK trafficking and an innovative therapeutic target in widespread applications.
This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.
This PDF is available to Subscribers Only