In addition to uncoupling eNOS and impairing endothelium-dependent vasodilation, excess ROS derived from NOX1 and NOX2 in the setting of hyperglycaemia also impairs NO production and bioavailability by increasing the production of superoxide anion, which reacts with NO to form peroxynitrite, which in turn oxidises the eNOS cofactor BH4 [30]. Here, NOS3 is linked to Hyperglycemia.