Neuron-derived netrin-1 and netrin-4 proteins are additional effective targets in diabetic retinopathy beyond VEGF

Vascular endothelial growth factor (VEGF) is the typical representative factor of diabetic retinopathy (DR) and is considered to be a key inducer of retinal vascular permeability in DR. Anti-VEGF has been widely used in clinical treatment but every patient is effective, therefore, it is necessary to find other effective factors that participate in the pathology of DR. We provide evidence from both human and animal experiments for the considerable roles of classical neuronal guidance factors, netrin-1 and netrin-4, in indicating and amending the pathology of DR. We reveal that levels of both netrin-1 and netrin-4 are reduced while VEGF increases in DR patients and animal models. We demonstrate through different experimental methods that augmenting netrin-1 and netrin-4 can alleviate vasculopathy and neuropathy which appear in DR. Our findings offer additional effect targets besides VEGF for DR and suggest we should increase the focus on neurovascular crosstalk as DR is a neurovascular disease.