Endothelium-Dependent Hyperpolarization (EDH) in Diabetes: Mechanistic Insights and Therapeutic Implications

Abstract

Diabetes mellitus is one of the major risk factors for cardiovascular disease and is an important health issue worldwide. Long-term diabetes causes endothelial dysfunction, which in turn leads to diabetic vascular complications. Endothelium-derived nitric oxide is a major vasodilator in large-size vessels, and the hyperpolarization of vascular smooth muscle cells mediated by the endothelium plays a central role in agonist-mediated and flow-mediated vasodilation in resistance-size vessels. Although the mechanisms underlying diabetic vascular complications are multifactorial and complex, impairment of endothelium-dependent hyperpolarization (EDH) of vascular smooth muscle cells would contribute at least partly to the initiation and progression of microvascular complications of diabetes. In this review, we present the current knowledge about the pathophysiology and underlying mechanisms of impaired EDH in diabetes in animals and humans. We also discuss potential therapeutic approaches aimed at the prevention and restoration of EDH in diabetes.

Keywords: Ca2+-activated K+ channel; antidiabetic agent; diabetes mellitus; endothelial function; endothelium-dependent hyperpolarization; endothelium-derived hyperpolarizing factor; gap junction; reactive oxygen species.

Figure 1

Endothelium-dependent hyperpolarization of vascular smooth muscle cells. Endothelial stimulation with agonists or by shear stress increases the intracellular Ca²⁺ concentration due to Ca²⁺ release from the endoplasmic reticulum (ER) and Ca²⁺ influx through endothelial nonselective cation channels of the transient receptor potential (TRP) family. The rise in the endothelial Ca²⁺ concentration subsequently activates small (SK_Ca) and intermediate conductance (IK_Ca) Ca²⁺-activated K⁺ channels, generating endothelium-dependent hyperpolarization (EDH). The EDH then spreads to adjacent smooth muscle cells via myoendothelial gap junctions (MEGJs), leading to vasorelaxation in a number of vascular beds. In some vascular beds, diffusible factors hyperpolarize vascular smooth muscle cells via the opening of potassium channels and/or activation of Na⁺/K⁺-ATPase. Diffusible factors also act on endothelial potassium channels to generate or amplify EDH in certain vascular beds in specific conditions.