Hyperglycemia-induced TET2 overexpression caused active demethylation of ROBO4 by oxidizing 5-methylcytosine to 5-hydroxymethylcytosine, which enhanced the binding of SP1 to ROBO4, increased the expression of ROBO4, and decreased the expression of ZO-1 and occludin, leading to the abnormalities in monolayer permeability, migratory ability and angiogenesis of HRECs. Here, SP1 is linked to Hyperglycemia.