Purpose 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 inretinal NV.
Methods The expression and effect of ephrin-A4 was investigated in a mouse model of oxygen-induced retinopathy (OIR) and the RF/6Aretina 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 invitro 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.
Results Ephrin-A4 was overexpressed in the retina of OIR mice and in RF/6Aand RPE cells after CoCl(2) stimulation. In vitro, Ephrin-A4/Fc treatment significantly increased the tube number of RF/6Acells on a membrane preparation and the phosphorylation levels of VEGR2, Akt1, and ERK1/2 inRF/6Acells. Moreover, ephrin-A4 knockout markedly suppressed pathologic neovascularization in vivo and inhibited the proliferation and tube formation capacity of RF/6Acells in vitro. Furthermore, in the absence of ephrin-A4, the phosphorylation of VEGFR2, Akt1, and ERK1/2 was defective under VEGF(165) stimulation, and the proangiogenic function of VEGF(165) was also compromised.
Conclusions 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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