EDH: endothelium-dependent hyperpolarization and microvascular signalling

Abstract

Endothelium-dependent hyperpolarizing factor (EDHF) is a powerful vasodilator influence in small resistance arteries and thus an important modulator of blood pressure and flow. As the name suggests, EDHF was thought to describe a diffusible factor stimulating smooth muscle hyperpolarization (and thus vasodilatation). However, this idea has evolved with the recognition that a factor can operate alongside the spread of hyperpolarizing current from the endothelium to the vascular smooth muscle (VSM). As such, the pathway is now termed endothelium-dependent hyperpolarization (EDH). EDH is activated by an increase in endothelial [Ca²⁺ ]_i , which stimulates two Ca²⁺ -sensitive K channels, SK_Ca and IK_Ca . This was discovered because apamin and charybdotoxin applied in combination blocked EDHF responses, but iberiotoxin - a blocker of BK_Ca - was not able to substitute for charybdotoxin. SK_Ca and IK_Ca channels are arranged in endothelial microdomains, particularly within projections towards the adjacent smooth muscle, which are rich in IK_Ca channels and close to interendothelial gap junctions where SK_Ca channels, are prevalent. K_Ca activation hyperpolarizes endothelial cells, and K⁺ efflux through them can act as a diffusible 'EDHF' by stimulating VSM Na⁺ ,K⁺ -ATPase and inwardly rectifying K channels (K_IR ). In parallel, hyperpolarizing current spreads from the endothelium to the smooth muscle through myoendothelial gap junctions located on endothelial projections. The resulting radial EDH is complemented by the spread of 'conducted' hyperpolarization along the endothelium of arteries and arterioles to affect conducted vasodilatation (CVD). Retrograde CVD effectively integrates blood flow within the microcirculation, but how the underlying hyperpolarization is sustained is unclear.

Keywords: IKC a; SKC a; KCa2.3; KCa3.1; connexins; gap-junctions; vasodilatation.