Macro‐ and microvascular endothelial dysfunction in diabetes

Highlights Diabetes affects endothelial function in both large blood vessels and the microvasculature. Diabetes‐induced endothelial dysfunction, especially in the microvasculature, is characterized by reduced nitric oxide ( NO ) bioavailability, increased oxidative stress, an imbalance between vascular endothelial growth factor ( VEGF ) and NO , and impairment of endothelial repair. Treatments targeting micro RNA s, specifically those interfering with the balance between VEGF and NO and endothelial progenitor cell function, may be promising therapeutic strategies in diabetes. Diabetes reduces endothelium‐dependent relaxations in conduit and resistance arteries. Diabetes‐induced endothelial dysfunction presents itself as a reduced protein expression of endothelial nitric oxide synthase (e NOS ), reduced phosphorylation of the active site of the e NOS (i.e. S er 1177 ; S ), increased phosphorylation of its inhibitory site (i.e. T hr 495 ; T ), decreased levels of the essential cofactor tetrahydrobiopterin ( BH 4 ), enhanced arginase activity, increased levels of asymmetric dimethylarginine ( ADMA ), and enhanced production of oxygen‐derived free radicals. Initially, prostacyclin ( PGI 2 ) and/or endothelium‐dependent hyperpolarization ( EDH ) take part in compensatory mechanisms when nitric oxide ( NO )‐mediated responses are impaired. AA , arachidonic acid; COX , cyclo‐oxygenase; HDL , high‐density lipoprotein; IP , prostacyclin receptor; ox LDL , oxidized low‐density lipoprotein; PGH 2 , prostaglandin H 2 ; R , receptor; TP , thromboxane receptor.