Endothelium-derived hyperpolarizing factor
In
Introduction
The endothelium maintains vascular
Pathways Of EDHF
There are two general pathways that explain EDH
- Diffusible factors are endothelium-derived substances that are able to pass through internal elastic layer (IEL), reach underlying vascular smooth muscle cells at a concentration sufficient to activate ion channels, and initiate smooth muscle hyperpolarization and relaxation.[1]
- Contact-mediated mechanisms bestow endothelial hyperpolarization that passively spreads to the smooth muscle through inter-cellular coupling, and, therefore, EDH is considered as a solely electrical event.[1]
Discovering the Chemical Identity
Although the phenomenon of EDHF has been observed and reported in scientific literature, to date the chemical identity of the factor(s) has not been determined.
- In some cases, members of a class of P450 epoxygenase enzymes.[2]
- In addition, in some cases hydrogen peroxide has been suggested to function as an EDHF in some vascular beds;[3] although the validity of this observation is debated[4] because it may have an inhibitory action on K+ channels, at least, in some vascular beds.[1]
- It has been suggested that EDHF is potassium ions (K+), as the activation of endothelial K-Ca+ channels causes an efflux of K+ from endothelial cells toward the extracellular space. An increase in extracellular K+ has been shown to activate an ouabain-sensitive electrogenic Na+–K+-ATPase followed by hyperpolarization and smooth muscle cell relaxation. However, the involvement of K+ ions in EDHF-mediated relaxation does not necessarily involve the activation Na+–K+-ATPase channels. It is more likely that K+ ions and gap junctions can be involved in EDHF-mediated relaxation simultaneously, and may also act synergistically.[1]
- Subsequently, it was suggested that EDHF is a sulfur signal that results in activation of K channels via sulfhydration of a cysteine residue (formation of a cysteine persulfide) (https://doi.org/10.1161/CIRCRESAHA.111.240242)
- C-type natriuretic peptide (CNP) has been shown to exert a variety of cardiovascular effects including vasodilation and hyperpolarization of arteries through the opening of KCa+-channels. CNP is widely distributed in the cardiovascular system and it has been found at high concentrations, in particular in endothelial cells. Endothelium-derived CNP has been proposed to act as an EDHF via specific C-subtype of natriuretic peptide receptor, however the evidence in favour of CNP's acting as EDHF has yet to be determined.[1]
- An alternative explanation for the EDHF phenomenon is that direct intercellular communication via gap junctions allows passive spread of agonist-induced endothelial hyperpolarization through the vessel wall. In some arteries, eicosanoids and K+ ions may themselves initiate a conducted endothelial hyperpolarization, thus suggesting that electrotonic signalling may represent a general mechanism through which the endothelium participates in the regulation of vascular tone.[5]
EDHF and Hypertension
Recently, EDHF has been implicated in gender-related differences in blood pressure control. The generation of animals that lack both
Summary
Based on current evidence, the term of endothelium-derived hyperpolarising factor should represent a mechanism rather than a specific factor. The mechanism(s) of endothelium-dependent hyperpolarization (i.e., EDHF-mediated relaxation) seems to be heterogeneous depending on several factors (e.g., size and vascular bed), surrounding environment (oxidative stress, hypercholesterolemia) and demand (compensatory). Different endothelial mediators or pathways involved in EDHF-mediated relaxation may also work simultaneously and/or substitute each other. It implies a reasonable physiological sense, although to some extent and when EDHF acts as backup mechanism for endothelium-dependent relaxation in the present of compromised NO contribution. Thus, alternatives for EDHF-typed responses (H2O2, K+ etc.) will provide a guarantee for compensation of endothelial function. However, once the involvement of a certain endothelium-derived vasodilator for a given vascular bed is confirmed, it is preferred that they be described by their proper name (i.e., endothelium-derived H2O2, or CNP), and no longer be termed as “EDHF”.[1] Although the role of EDHF in the genesis of Cardiovascular Disease remains to be further elucidated, the EDHF contribution and its importance at the level of small arteries delivers a theoretical opportunity to control systemic blood pressure. There is an increasing experimental evidence to suggest that treatment of the EDHF system could provide a means to control blood pressure and blood flow to target organs in compatible way achieved by manipulations of NO system.
Since “EDHF story” is particularly heterogeneous and based mainly on animal studies, the most important and demanding current task is to strengthen our knowledge about EDHF action in human arteries in health and disease.[6]