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Félétou M. The Endothelium: Part 2: EDHF-Mediated Responses “The Classical Pathway”. San Rafael (CA): Morgan & Claypool Life Sciences Publisher; 2011.

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The Endothelium: Part 2: EDHF-Mediated Responses “The Classical Pathway”.

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Endothelial cells control the tone of the underlying vascular smooth muscle by releasing numerous vasoactive substances, including NO, reactive oxygen species, metabolites of arachidonic acid (e.g; prostacyclin, EETs, lipoxygenase derivatives), peptides, etc. Furthermore, the endothelial monolayer behaves as a conductive tissue propagating an electrical signal along the axis of the blood vessel by means of homocellular gap junctions and throughout the vascular wall itself by means of myo-endothelial gap junctions (Figure 9). EDHF-mediated responses appear to play a major role in peripheral blood vessels and in the coronary, cerebral and renal circulation, and may, under some circumstances, act as a back-up system when NO is inhibited or reduced. EDHF-mediated responses should not be considered as an independent phenomenon, since, as with other endothelial pathways, interplay and inter-regulation are more the rule than the exception. Endothelial key enzyme and ion channels driving EDHF-mediated responses also stimulate eNOS activation and most likely arachidonic acid metabolism by amplifying intracellular Ca2+ signaling. Conversely, NO, H2O2, EETs can interact with multiple targets of EDHF-mediated responses. Attention is now focusing on the microdomains in which endothelial SKCa and IKCa channels are located and particularly on how various stimuli, modulating the activation of SKCa in caveolae and that of IKCa in endothelial projections, contribute to changes in smooth muscle tone and consequently, in blood vessel diameter and changes in blood flow.

FIGURE 9. Endothelium-dependent relaxations and contractions.


Endothelium-dependent relaxations and contractions. Endothelial cells synthesize and release various vasoactive factors and therefore maintain the balance between vasodilatation and vasoconstriction. Upsetting this tightly regulated balance contributes (more...)

A decrease in NO bioavailability or function is associated with most of the endothelial dysfunctions observed in virtually all cardiovascular diseases. However, EDHF-mediated responses are also affected by various pathological situations, although the changes observed appears highly complex and seem to depend on the model, the vascular tissue studied, the experimental conditions and so on. However, this apparent complexity is intrinsically linked to the various endothelial mechanisms, which, in addition to the “classical” EDHF-mediated responses, are involved in endothelium-dependent vasodilatations and are still confusingly termed “EDHF”, including metabolites of arachidonic acid, H2O2, gaseous mediators and putative vasodilatory peptide(s). These various mechanisms are differently regulated and do not change in unison. For instance, NO inhibits cytochrome P450 activity, and therefore NOS uncoupling can lead to the production of EETs. Furthermore, NOS uncoupling can also favor the generation of H2O2. Whether or not NO and/or reactive oxygen species affect the various elements involved in the “classical” EDHF-mediated responses remains basically unknown.

However, an important feature that emerges from recent studies is the regulatory role of endothelial potassium channel expression/activity. In various pathological animal models of hypertension (SHR, SHR-SP, angiotensin-II infused) and type-II diabetes/obesity (Zucker and cafetaria diet-induced obesity), maintenance or up-regulation of the activity of IKCa channels, at time associated with an increase expression of IK1, has been reported, while the reverse is observed for the SKCa channel [162,204,543,601,647,1670], suggesting that IKCa channels are the last line of defense maintaining endothelium-dependent vasodilatation. IK1 expression is negatively regulated by the repressor element-1 silencing transcription factor (REST) [245,1543]. In SHR-SP a decreased REST expression may explain the up-regulation of IK1 [543], while, in Fabri's disease, a lysosomal storage disease caused by defects in α-galactosidase, the endothelial dysfunction has been associated with up-regulation of REST-1 and reduced expression of IK1 [317,1191]. It remains to be determined whether or not this mechanism could be a more general process regulating EDHF-mediated relaxations in cardiovascular diseases.

Although, the improvement or restoration of EDHF responses has not yet been the direct purpose of any pharmaceutical effort, some existing therapeutic interventions appears to improve these responses suggesting that this effect could contribute to their therapeutic benefice. However, the mechanisms underlying these putative beneficial effects are poorly understood. In order to determine whether or not new therapeutic targets can be identified within the “classical” EDHF pathway, a better understanding of its role in physiological condition and in diseases must be achieved. Unfortunately, it is often difficult to reach a conclusion as to the true importance of endothelium-dependent hyperpolarizations because of the use of unspecific pharmacological tools and the lack of electrophysiological measurements. The limited information available suggests that if better (i.e. more potent, more specific and if possible orally active) pharmacological tools were developed to modulate the role of the various molecular constituents underlying EDHF-mediated responses, it may be possible to determine their physiological role in the human circulation. Finally, it would be of utmost importance to determine if EDHF-mediated responses, could, besides the regulation of vascular tone, play a role in other(s) of the multiple functions of the endothelial cells, as various endothelium-derived vasoactive substances do.

Copyright © 2011 by Morgan & Claypool Life Sciences Publisher.
Bookshelf ID: NBK57105
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