Endothelial dysfunction plays a key role in the pathogenesis of diabetic va
scular disease. The endothelium controls the tone of the underlying vascula
r smooth muscle through the production of vasodilator mediators. The endoth
elium-derived relaxing factors (EDRF) comprise nitric oxide (NO), prostacyc
lin, and a still elusive endothelium-derived hyperpolarizing factor (EDHF).
Impaired endothelium-dependent vasodilation has been demonstrated in vario
us vascular beds of different animal models of diabetes and in humans with
type 1 and 2 diabetes. Several mechanisms of endothelial dysfunction have b
een reported, including impaired signal transduction or substrate availibil
ity, impaired release of EDRF, increased destruction of EDRF, enhanced rele
ase of endothelium-derived constricting factors and decreased sensitivity o
f the vascular smooth muscle to EDRF. The principal mediators of hyperglyca
emia-induced endothelial dysfunction may be activation of protein kinase C,
increased activity of the polyol pathway, non-enzymatic glycation and oxid
ative stress. Correction of these pathways, as well as administration of AC
E inhibitors and folate, has been shown to improve endothelium-dependent va
sodilation in diabetes. Since the mechanisms of endothelial dysfunction app
ear to differ according to the diabetic model and the vascular bed under st
udy, it is important to select clinically relevant models for future resear
ch of endothelial dysfunction.