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Wei Du, Wenzhen Yu, Lvzhen Huang, Min Zhao, Xiaoxin Li; Ephrin-A4 Is Involved in Retinal Neovascularization by Regulating the VEGF Signaling Pathway. Invest. Ophthalmol. Vis. Sci. 2012;53(4):1990-1998. doi: https://doi.org/10.1167/iovs.11-8788.
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© ARVO (1962-2015); The Authors (2016-present)
Retinal neovascularization (NV) is a major cause of blindness. Recent research suggests that factors other than VEGF participate in this process. This study aimed to determine the role of ephrin-A4 in retinal NV.
The expression and effect of ephrin-A4 was investigated in a mouse model of oxygen-induced retinopathy (OIR) and the RF/6A retina endothelial cell line. Ephrin-A4 expression and VEGF signaling pathway phosphorylation were determined by PCR, immunohistochemistry, and western blot analyses. ShRNA was used to silence ephrin-A4 in vitro and in vivo. Retinal flat mounts and tube formation assays were performed to evaluate ephrin-A4 function in the NV process in vivo and in vitro.
Ephrin-A4 was overexpressed in the retina of OIR mice and in RF/6A and RPE cells after CoCl2 stimulation. In vitro, Ephrin-A4/Fc treatment significantly increased the tube number of RF/6A cells on a membrane preparation and the phosphorylation levels of VEGR2, Akt1, and ERK1/2 in RF/6A cells. Moreover, ephrin-A4 knockout markedly suppressed pathologic neovascularization in vivo and inhibited the proliferation and tube formation capacity of RF/6A cells in vitro. Furthermore, in the absence of ephrin-A4, the phosphorylation of VEGFR2, Akt1, and ERK1/2 was defective under VEGF165 stimulation, and the proangiogenic function of VEGF165 was also compromised.
This study suggests that ephrin-A4 plays an important role in retinal NV and is a potential target against retinal NV. The proangiogenic function of ephrin-A4 may be linked to its crucial role in the VEGF signaling pathway.
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