Endothelium-Derived Hyperpolarizing Factors: A Potential Therapeutic Target for Vascular Dysfunction in Obesity and Insulin Resistance

The endothelium consists of a single layer of cells that serves as a barrier between blood and tissues and actively participates in the regulation of vascular tone and function (1). The influence of the endothelium on blood flow in arterioles and capillaries is modulated by the synthesis and release of a number of endothelial-derived relaxing and constricting substances such as nitric oxide (NO), prostacyclin (PGI2), and endothelium-derived hyperpolarizing factors (EDHF) (2). However, the balance or homeostasis between endothelial relaxing and constricting factors is disrupted in insulin-resistant states including obesity, type 2 diabetes mellitus (T2DM), and hypertension, all of which promote cardiovascular disease (CVD) (1,2). For example, endothelial cell (EC) dysfunction is caused by impairment of endothelial-dependent vasodilation in various vascular beds such as skeletal muscle arterioles and capillaries. Both conduit arteries and microvessels are very important for insulin and glucose metabolism as an increase in capillary surface area prompts both insulin and glucose delivery and subsequent glucose uptake in skeletal muscle tissue (3,4). In healthy individuals, systemic and local infusion of insulin induces NO production to prompt insulin-mediated capillary recruitment and microvascular blood flow, resulting in an increase in forearm blood volume (2). One study demonstrated that endothelial NO synthase inhibition significantly blunted the insulin-stimulated increase of ultrasound-assessed femoral blood flow without any changes in blood pressure and heart rate in rats (5). In parallel, insulin-stimulated capillary recruitment and glucose uptake were completely abolished (5), suggesting that local capillary NO bioavailability plays a key role in the regulation of insulin-stimulated skeletal muscle capillary recruitment and glucose uptake. The …