The effects of diabetes on vascular function and potential treatment with a flavonol

Endothelial cells, lining all blood vessels, can release both relaxing and contracting factors to modulate the tone of the underlying smooth muscle. Endothelium-dependent relaxation is mediated by multiple factors including nitric oxide (NO), prostacyclin and an unidentified endothelium-derived hyperpolarizing factor (EDHF). Diabetes mellitus is characterized by hyperglycaemia resulting from a defective secretion or action of endogenous insulin. It is well established that diabetes often causes macro- and microvascular complications in human and animal models of diabetes, and several lines of evidence suggest that endothelial dysfunction could play a critical and initiating role in the development of these complications. It remains unclear how the relative contribution of endothelium-derived factors to relaxation were modulated over the course of diabetes-induced hyperglycaemia. The aim of this thesis was to examine the effects of early and later stages of diabetes on vascular function, and to explore the potential use of a flavonol as an alternative treatment for diabetic vascular diseases. This thesis provided further insights in the pathological process underlying endothelial dysfunction in both macro- and microvasculature over the duration of hyperglycaemia. At the early stages of diabetes, hyperglycaemia caused oxidative stress through the increase in NADPH oxidase expression/activity and endothelial NO synthase (eNOS) uncoupling but endothelial function was maintained. At the later stages of diabetes, the increase in NADPH oxidase expression/activity and eNOS uncoupling continued to contribute to oxidative stress, suggesting that the increase in NADPH oxidase expression/activity and eNOS uncoupling are an early contributor to hyperglycaemia-induced endothelial dysfunction. Endothelial dysfunction is associated with an impairment of both NO and EDHF. Short term treatment with a novel antioxidant, 3’,4’-dihydroxyflavonol (DiOHF) in diabetic rats had no effect on the glycaemic levels, indicating that DiOHF improves vascular function via a glucose lowering-independent pathway. The protective actions of DiOHF occur through at least two mechanisms: DiOHF is able to rapidly scavenge ROS and/or inhibit the enzymatic source for superoxide production (i.e. NADPH oxidase and eNOS uncoupling). Treatment with DiOHF improves endothelial function primarily through the preservation of NO function. The ability of DiOHF to inhibit superoxide production derived from NADPH oxidase and eNOS uncoupling makes it a potential adjunctive treatment for diabetic vascular complications