ANGPT2 and Hyperglycemia: [25] In the very early stage, angiopoietin-2 is known to be upregulated in response to hyperglycemia to induce and exaggerate pericyte dropout. High glucose levels cause ROS overproduction, which also damages endothelial cells and leads to further vasoregression. [26] After hypoxia becomes evident as a result of vasoregression, VEGF and angiopoietin-2 cooperate to induce endothelial cell proliferation, pericyte activation, and finally neovascularization [27], the PDR stage.