NOS3 and Hyperglycemia: Hyperglycemia induces changes in a variety of cellular signaling and metabolic pathways including altered hemodynamics due to decreased eNOS activity and increased ET-1 synthesis, increased oxidative stress and inflammation, basement membrane thickening caused by transforming growth factor-β (TGF-β) mediated increased synthesis of collagen IV and fibronectin, extracellular matrix changes, VEGF-induced damage to VSMC vascular permeability, cellular growth, inhibition of protein kinase B (PKB, also known as Akt) activation, angiogenesis, and decrease of Na+-K+-ATPase activity 79-81.