In
blood vessels
The blood vessels are the components of the circulatory system that transport blood throughout the human body. These vessels transport blood cells, nutrients, and oxygen to the tissues of the body. They also take waste and carbon dioxide away f ...
Endothelium-Derived Hyperpolarizing Factor or EDHF is proposed to be a substance and/or electrical signal that is generated or synthesized in and released from the
endothelium
The endothelium is a single layer of squamous endothelial cells that line the interior surface of blood vessels and lymphatic vessels. The endothelium forms an interface between circulating blood or lymph in the lumen and the rest of the vessel ...
; its action is to
hyperpolarize vascular
smooth muscle cells
Smooth muscle is an involuntary non-striated muscle, so-called because it has no sarcomeres and therefore no striations (''bands'' or ''stripes''). It is divided into two subgroups, single-unit and multiunit smooth muscle. Within single-unit mus ...
, causing these cells to relax, thus allowing the blood vessel to expand in diameter.
Introduction
The endothelium maintains vascular
homeostasis
In biology, homeostasis (British English, British also homoeostasis) Help:IPA/English, (/hɒmɪə(ʊ)ˈsteɪsɪs/) is the state of steady internal, physics, physical, and chemistry, chemical conditions maintained by organism, living systems. Thi ...
through the release of active
vasodilators
Vasodilation is the widening of blood vessels. It results from relaxation of smooth muscle cells within the vessel walls, in particular in the large veins, large arteries, and smaller arterioles. The process is the opposite of vasoconstriction, ...
. Although
nitric oxide
Nitric oxide (nitrogen oxide or nitrogen monoxide) is a colorless gas with the formula . It is one of the principal oxides of nitrogen. Nitric oxide is a free radical: it has an unpaired electron, which is sometimes denoted by a dot in its che ...
(NO) is recognized as the primary factor at level of arteries, increased evidence for the role of another endothelium-derived vasodilator known as endothelium-derived hyperpolarizing factor (EDHF) has accumulated in the last years. Experiments show that when NO and
Prostacyclin
Prostacyclin (also called prostaglandin I2 or PGI2) is a prostaglandin member of the eicosanoid family of lipid molecules. It inhibits platelet activation and is also an effective vasodilator.
When used as a drug, it is also known as epoprosteno ...
(Vasodilators) are inhibited there is still another factor causing the vessels to dilate
Despite the ongoing debate of its intriguingly variable nature and mechanisms of action, the contribution of EDHF to the endothelium-dependent relaxation is currently appreciated as an important feature of “healthy” endothelium. Since EDHF's contribution is greatest at level of small arteries, the changes in the EDHF action are of critical importance for the regulation of organ blood flow,
peripheral vascular resistance
Vascular resistance is the resistance that must be overcome to push blood through the circulatory system and create flow. The resistance offered by the systemic circulation is known as the systemic vascular resistance (SVR) or may sometimes be cal ...
, and
blood pressure
Blood pressure (BP) is the pressure of circulating blood against the walls of blood vessels. Most of this pressure results from the heart pumping blood through the circulatory system. When used without qualification, the term "blood pressure" r ...
, and in particular when production of NO is compromised. Moreover, depending on the type of cardiovascular disorders altered, EDHF responses may contribute to, or compensate for, endothelial abnormalities associated with pathogenesis of certain diseases.
It is widely accepted EDHF plays an important role in vasotone, especially in micro vessels. Its effect varies, depending on the size of the vessel.
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
Ion channels are pore-forming membrane proteins that allow ions to pass through the channel pore. Their functions include establishing a resting membrane potential, shaping action potentials and other electrical signals by gating the flow of io ...
, and initiate smooth muscle hyperpolarization and relaxation.
* 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.
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
arachidonic acid
Arachidonic acid (AA, sometimes ARA) is a polyunsaturated omega-6 fatty acid 20:4(ω-6), or 20:4(5,8,11,14). It is structurally related to the saturated arachidic acid found in cupuaçu butter. Its name derives from the New Latin word ''arachi ...
derivatives, the
epoxyeicosatrienoic acid
The epoxyeicosatrienoic acids or EETs are signaling molecules formed within various types of cells by the metabolism of arachidonic acid by a specific subset of Cytochrome P450 enzymes termed cytochrome P450 epoxygenases. These nonclassic eicosa ...
s (EETs), have been found to mediate the vasodilation. These compounds are formed by
epoxidation
In organic chemistry, an epoxide is a cyclic ether () with a three-atom ring. This ring approximates an equilateral triangle, which makes it strained, and hence highly reactive, more so than other ethers. They are produced on a large scale for ...
of any one of four
double bond
In chemistry, a double bond is a covalent bond between two atoms involving four bonding electrons as opposed to two in a single bond. Double bonds occur most commonly between two carbon atoms, for example in alkenes. Many double bonds exist betw ...
s of the arachidonic acid carbon backbone by
cytochrome
Cytochromes are redox-active proteins containing a heme, with a central Fe atom at its core, as a cofactor. They are involved in electron transport chain and redox catalysis. They are classified according to the type of heme and its mode of bin ...
P450
Cytochromes P450 (CYPs) are a superfamily of enzymes containing heme as a cofactor that functions as monooxygenases. In mammals, these proteins oxidize steroids, fatty acids, and xenobiotics, and are important for the clearance of various compo ...
epoxygenase
Epoxygenases are a set of membrane-bound, heme-containing cytochrome P450 (CYP P450 or just CYP) enzymes that metabolize polyunsaturated fatty acids to epoxide products that have a range of biological activities. The most thoroughly studied substr ...
enzymes.
* In addition, in some cases
hydrogen peroxide
Hydrogen peroxide is a chemical compound with the formula . In its pure form, it is a very pale blue liquid that is slightly more viscous than water. It is used as an oxidizer, bleaching agent, and antiseptic, usually as a dilute solution (3% ...
has been suggested to function as an EDHF in some vascular beds;
although the validity of this observation is debated
because it may have an inhibitory action on K+ channels, at least, in ''some'' vascular beds.
* 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
Extracellular space refers to the part of a multicellular organism outside the cells, usually taken to be outside the plasma membranes, and occupied by fluid. This is distinguished from intracellular space, which is inside the cells.
The compositi ...
. An increase in extracellular K
+ has been shown to activate an
ouabain
Ouabain or (from Somali ''waabaayo'', "arrow poison" through French ''ouabaïo'') also known as g-strophanthin, is a plant derived toxic substance that was traditionally used as an arrow poison in eastern Africa for both hunting and warfare. ...
-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.
* 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
Natriuretic peptide precursor C, also known as NPPC, is a protein that in humans is encoded by the ''NPPC'' gene. The precursor NPPC protein is cleaved to the 22 amino acid peptide C-type natriuretic peptide (''CNP'').
Function
Natriuretic pe ...
(CNP) has been shown to exert a variety of cardiovascular effects including vasodilation and hyperpolarization of arteries through the opening of K
Ca+-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.
* An alternative explanation for the EDHF phenomenon is that direct intercellular communication via
gap junction
Gap junctions are specialized intercellular connections between a multitude of animal cell-types. They directly connect the cytoplasm of two cells, which allows various molecules, ions and electrical impulses to directly pass through a regulate ...
s 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.
EDHF and Hypertension
Recently, EDHF has been implicated in gender-related differences in blood pressure control. The generation of animals that lack both
endothelial nitric oxide synthase
Endothelial NOS (eNOS), also known as nitric oxide synthase 3 (NOS3) or constitutive NOS (cNOS), is an enzyme that in humans is encoded by the ''NOS3'' gene located in the 7q35-7q36 region of chromosome 7. This enzyme is one of three isoforms tha ...
(eNOS) and
COX-1
Cyclooxygenase 1 (COX-1), also known as prostaglandin G/H synthase 1, prostaglandin-endoperoxide synthase 1 or prostaglandin H2 synthase 1, is an enzyme that in humans is encoded by the ''PTGS1'' gene. In humans it is one of two cyclooxygenases.
...
(Cyclooxygenase-1, a protein that acts as an enzyme to speed up the production of certain chemical messengers), has allowed a direct assessment of the involvement of EDHF to endothelium-dependent relaxation in small arteries. In mice lacking both eNOS and COX-1, EDHF-mediated response appeared to compensate the absence of endothelial NO in females but not in males. In female mice, the deletion of eNOS and COX-1 did not affect mean arterial blood pressure, while males become hypertensive
In accordance with this study, EDHF has been suggested to be more important in female arteries to confer endothelium-dependent dilatation, while NO played a predominant role in arteries from males. The latter finding indeed concurs with previous reports in several vascular beds, including mesenteric and tail arteries from rats as well as genital arteries from rabbits. These findings together suggest that under pathological conditions EDHF could compensate for the loss of NO in female rather than in male arteries
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 (H
2O
2, 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 H
2O
2, or CNP), and no longer be termed as “EDHF”.
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.
See also
*
Endothelium-derived relaxing factor
Endothelium-derived relaxing factor (EDRF) is a name for a Chemical substance, substance that Robert F. Furchgott discovered had the eponymous properties. Today, it is firmly established this substance is nitric oxide (NO). Endothelium produces NO ...
References
{{reflist, 2
Biomolecules
Vasodilators
Angiology