Endothelium-derived hyperpolarizing factor in vascular physiology and cardiovascular disease

Abstract

The endothelium maintains vascular homeostasis through the release of active vasodilators. Although nitric oxide (NO) is recognized as the primary factor at level of conduit arteries, increased evidence for the role of another endothelium-derived vasodilator known as endothelium-derived hyperpolarizing factor (EDHF) has accumulated in the last years. 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 particularly 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 disease. Consequently, an identification of vessel-specific nature of EDHF, its modulation of biological activity by selective activators or inhibitors might have a significant impact to our understanding of vascular maintenance in health and disease, and provide basis for novel therapeutic strategies. In this review, the contemporary knowledge about mechanism, function and dysfunction of EDHF-typed responses is systemized. The relevance of this part of endothelium-dependent relaxation for main cardiovascular complications is under discussion. Several issues, like gender differences and role of estrogen for EDHF contribution are summarized for the first time. Authors based on their own experience and data of literature propose several guidelines for future research in the field of EDHF.

Introduction

More than a quarter of a century passed since discovery of the vital importance of endothelium for vascular control [1]. Prostacyclin (PGI₂)—a cyclooxygenase-dependent metabolite of arachidonic acid (AA) [2] and nitric oxide (NO) formed through l-arginine and NO synthase (NOS) pathway [3] were identified as major endothelium-derived vasodilators. However, the fact that NO and PGI₂ could not fully account for the agonist-induced relaxation has suggested the existence of an additional mechanism defined as endothelium-dependent but NO and PGI₂ independent [4], [5]. Since the residual endothelium-dependent relaxation is concurrent with vascular smooth muscle cell (VSMC) hyperpolarization and abolished by potassium channel (K⁺-channel) blockers or by depolarizing concentration of K⁺, the mediator responsible for this occurrence was termed as endothelium-derived hyperpolarizing factor (EDHF) [6]. Thus, by definition, EDHF seems to be a substance and/or electrical signal that is generated or synthesized in and released from the endothelium that hyperpolarizes VSMC followed by relaxation [7], [8].

The EDHF predominantly confers endothelium-dependent modulation of VSMC tone in resistance-sized arteries [9]. EDHF-mediated contribution to endothelium-dependent dilatation increases as the vessel size decreases [10], [11] (Fig. 1), although the variability between species and vascular beds is observed. For example, different contribution of EDHF vs. NO has been shown between small arteries isolated from coronary, mesenteric and skeletal muscle vascular beds of hamster [12]. The functional evidence is strengthened by electrophysiological experiments, in which endothelium-dependent changes in membrane potential are more pronounced in smaller vs. large arteries [10]. An inverse relationship between endothelial NOS (eNOS) expression and vessel size in the aorta and proximal vs. distal mesenteric arteries also exists [13].

Since EDHF-mediated responses are most prominent after NOS inhibition, it might be suggested that the continuous production of NO by endothelial cells (EC) could damp out the generation of EDHF and/or mechanism of its action. Hypothetically EDHF may act as a backup endothelium-derived vasodilator when NO production is compromised. In small mesenteric arteries from mice deficient in eNOS, an up-regulation of EDHF contribution occurs [14]. Exogenously applied NO at concentrations compatible to those achieved after stimulation with endothelium-dependent agonist attenuates EDHF-mediated dilatations in rabbit carotid and porcine coronary arteries, and the effect is likely to be due to interference with synthesis and/or release of EDHF rather than its action per se[15].