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ABSTRACT: EDHF (endothelium-derived hyperpolarizing factor) was envisaged as a chemical entity causing vasodilation by hyperpolarizing vascular smooth muscle cells (VSM) and distinct from nitric oxide (aka EDRF) and prostacyclin. The search for an identity for EDHF unravelled the complexity of signalling within small arteries. Hyperpolarization originates within endothelial cells (ECs), spreading to the VSM by two branches, one chemical and one electrical, with the relative contribution varying with artery location, branch order and prevailing profile of VSM activation. Chemical signals vary likewise and can involve potassium ion, lipid mediators and hydrogen peroxide, whereas electrical signalling depends on physical contacts formed by homo and hetero-cellular (myoendothelial; MEJ) gap-junctions, both able to conduct hyperpolarizing current. The discovery that chemical and electrical signals each arise within ECs resulted in an evolution of the single EDHF concept into the more inclusive, EDH signalling. Recognition of the importance of MEJs and particularly the fact they can support bidirectional signalling also informed the discovery that Ca2+ signals can pass from VSM to ECs during vasoconstriction. This signalling activates negative feedback mediated by NO and EDH forming a myoendothelial feedback circuit (MEF), which may also be responsible for basal or constitutive release of NO and EDH activity. The MEJs are housed in endothelial projections (MEPs), and another spin-off from investigating EDH signalling was the discovery these fine structures contain clusters of signalling proteins to regulate both hyperpolarization and NO release. So these tiny membrane bridges serve as a signalling superhighway or infobahn, which controls vasoreactivity by responding to signals flowing back and forth between the endothelium and VSM. By allowing bi-directional signalling, MEJs enable sinusoidal vasomotion, coordinated cycles of widespread vasoconstriction/vasodilation that optimize time-averaged blood flow. Cardiovascular disease disrupts EC signalling and as a result vasomotion changes to vasospasm.

Original publication




Journal article


J Cardiovasc Pharmacol

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