Endothelium-derived hyperpolarizing factor

In blood vessels 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; its action is to hyperpolarize vascular smooth muscle cells, causing these cells to relax, thus allowing the blood vessel to expand in diameter.[1]

Introduction

The endothelium maintains vascular homeostasis through the release of active vasodilators. Although Nitric Oxide (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 (Vasodilators) are inhibited there is still another factor causing the vessels to dilate[1] 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, and blood pressure, 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.[1]

Pathways Of EDHF

There are two general pathways that explain EDH

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.

EDHF and Hypertension

Recently, EDHF has been implicated in gender-related differences in blood pressure control. The generation of animals that lack both Endothelium Nitric Oxide Synthase (eNOS) and COX-1 (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[1] 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[1]

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 extend 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]

See also

References

  1. 1 2 3 4 5 6 7 8 9 10 11 Luksha L, Agewall S, Kublickiene K (February 2009). "Endothelium-derived hyperpolarizing factor in vascular physiology and cardiovascular disease". Atherosclerosis 202 (2): 330–44. doi:10.1016/j.atherosclerosis.2008.06.008. PMID 18656197.
  2. Pharmacol Rev. 2014 Oct;66(4):1106-40. doi: 10.1124/pr.113.007781. Review. PMID 25244930
  3. Shimokawa H, Morikawa K (November 2005). "Hydrogen peroxide is an endothelium-derived hyperpolarizing factor in animals and humans". J. Mol. Cell. Cardiol. 39 (5): 725–32. doi:10.1016/j.yjmcc.2005.07.007. PMID 16122755.
  4. You J, Golding EM, Bryan RM (September 2005). "Arachidonic acid metabolites, hydrogen peroxide, and EDHF in cerebral arteries". Am. J. Physiol. Heart Circ. Physiol. 289 (3): H1077–83. doi:10.1152/ajpheart.01046.2004. PMID 15863454.
  5. Griffith,TM (January 2004). "Endothelium-dependent smooth muscle hyperpolarization: do gap junctions provide a unifying hypothesis?". British Journal of Pharmacology 141 (6): 881–903. doi:10.1038/sj.bjp.0705698. PMC 1574270. PMID 15028638.
  6. Endothelium-derived hyperpolarizing factor in vascular physiology and cardiovascular disease Atherosclerosis, Volume 202, Issue 2, Pages 330-344 L. Luksha, S. Agewall, K. Kublickiene
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