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The term endothelium-derived hyperpolarising factor (EDHF) was introduced in 1987 to describe the hypothetical factor responsible for myocyte hyperpolarisations not associated with nitric oxide (EDRF) or prostacyclin. Two broad categories of EDHF response exist. The classical EDHF pathway is blocked by apamin plus TRAM-34 but not by apamin plus iberiotoxin and is associated with endothelial cell hyperpolarisation. This follows an increase in intracellular [Ca 2+ ] and the opening of endothelial SK Ca and IK Ca channels preferentially located in caveolae and in endothelial cell projections through the internal elastic lamina, respectively. In some vessels, endothelial hyperpolarisations are transmitted to myocytes through myoendothelial gap junctions without involving any EDHF. In others, the K + that effluxes through SK Ca activates myocytic and endothelial Ba 2+ -sensitive K IR channels leading to myocyte hyperpolarisation. K + effluxing through IK Ca activates ouabain-sensitive Na + /K + -ATPases generating further myocyte hyperpolarisation. For the classical pathway, the hyperpolarising “factor” involved is the K + that effluxes through endothelial K Ca channels. During vessel contraction, K + efflux through activated myocyte BK Ca channels generates intravascular K + clouds. These compromise activation of Na + /K + -ATPases and K IR channels by endothelium-derived K + and increase the importance of gap junctional electrical coupling in myocyte hyperpolarisations. The second category of EDHF pathway does not require endothelial hyperpolarisation. It involves the endothelial release of factors that include NO, HNO, H 2 O 2 and vasoactive peptides as well as prostacyclin and epoxyeicosatrienoic acids. These hyperpolarise myocytes by opening various populations of myocyte potassium channels, but predominantly BK Ca and/or K ATP , which are sensitive to blockade by iberiotoxin or glibenclamide, respectively.

The first endothelium-derived relaxing factor (EDRF) ever identified is a gasotransmitter, nitric oxide (NO). Recent studies have provided several lines of evidence to support the premise that hydrogen sulfide (H2S), another gasotransmitter, is a new EDRF. H2S production is catalyzed in mammalian cells by cystathionine β-synthase (CBS) and/or cystathionine γ-lyase (CSE). The expression of CSE proteins and the activity of CBS have been observed in vascular endothelial cells. A measurable amount of H2S is produced from endothelium upon muscarinic cholinergic stimulation. The endothelium-dependent vasorelaxation induced by H2S shares many common mechanistic traits with those of endothelium-derived hyperpolarizing factor (EDHF). Deficiency in CSE expression increases blood pressure in CSE knockout mice and significantly diminishes endothelium-dependent relaxation of resistance arteries. More extensive and mechanistic studies in the future will help to determine whether H2S is a new EDRF or the very EDHF.

Background: Aging leads to structural and functional changes in the vasculature characterized by arterial endothelial dysfunction and stiffening of large elastic arteries and is a predominant risk factor for cardiovascular disease, the leading cause of morbidity and mortality in modern societies. Although exercise reduces the risk of many age-related diseases, including cardiovascular disease, the mechanisms underlying the beneficial effects of exercise on age-related endothelial function fully elucidated. Purpose: The present study explored the effects of exercise on the impaired endothelium-derived hyperpolarizing factor (EDHF)–mediated vasodilation in aged arteries and on the involvement of the transient receptor potential vanilloid 4 (TRPV4) channel and the small-conductance calcium-activated potassium (KCa2.3) channel signaling in this process. Methods: Male Sprague-Dawley rats aged 19–21 months were randomly assigned to a sedentary group or to an exercise group. Two-month-old rats were used as young controls. Results: We found that TRPV4 and KCa2.3 isolated from primary cultured rat aortic endothelial cells pulled each other down in co-immunoprecipitation assays, indicating that the two channels could physically interact. Using ex vivo functional arterial tension assays, we found that EDHF-mediated relaxation induced by acetylcholine or by the TRPV4 activator GSK1016790A was markedly decreased in aged rats compared with that in young rats and was significantly inhibited by TRPV4 or KCa2.3 blockers in both young and aged rats. However, exercise restored both the age-related and the TRPV4-mediated and KCa2.3-mediated EDHF responses. Conclusion: These results suggest an important role for the TRPV4-KCa2.3 signaling undergirding the beneficial effect of exercise to ameliorate age-related arterial dysfunction.

It is becoming increasingly evident that electrical signaling via gap junctions plays a central role in the physiological control of vascular tone via two related mechanisms (1) the endothelium-derived hyperpolarizing factor (EDHF) phenomenon, in which radial transmission of hyperpolarization from the endothelium to subjacent smooth muscle promotes relaxation, and (2) responses that propagate longitudinally, in which electrical signaling within the intimal and medial layers of the arteriolar wall orchestrates mechanical behavior over biologically large distances. In the EDHF phenomenon, the transmitted endothelial hyperpolarization is initiated by the activation of Ca 2+ -activated K + channels channels by InsP 3 -induced Ca 2+ release from the endoplasmic reticulum and/or store-operated Ca 2+ entry triggered by the depletion of such stores. Pharmacological inhibitors of direct cell-cell coupling may thus attenuate EDHF-type smooth muscle hyperpolarizations and relaxations, confirming the participation of electrotonic signaling via myoendothelial and homocellular smooth muscle gap junctions. In contrast to isolated vessels, surprisingly little experimental evidence argues in favor of myoendothelial coupling acting as the EDHF mechanism in arterioles in vivo. However, it now seems established that the endothelium plays the leading role in the spatial propagation of arteriolar responses and that these involve poorly understood regenerative mechanisms. The present review will focus on the complex interactions between the diverse cellular signaling mechanisms that contribute to these phenomena.

Numerous studies indicate that regular intake of polyphenol-rich beverages (red wine and tea) and foods (chocolate, fruit, and vegetables) is associated with a protective effect on the cardiovascular system in humans and animals. Beyond the well-known antioxidant properties of polyphenols, several other mechanisms have been shown to contribute to their beneficial cardiovascular effects. Indeed, both experimental and clinical studies indicate that polyphenols improve the ability of endothelial cells to control vascular tone. Experiments with isolated arteries have shown that polyphenols cause nitric oxide (NO)-mediated endothelium-dependent relaxations and increase the endothelial formation of NO. The polyphenol-induced NO formation is due to the redox-sensitive activation of the phosphatidylinositol3-kinase/Akt pathway leading to endothelial NO synthase (eNOS) activation subsequent to its phosphorylation on Ser 1177. Besides the phosphatidylinositol3-kinase/Akt pathway, polyphenols have also been shown to activate eNOS by increasing the intracellular free calcium concentration and by activating estrogen receptors in endothelial cells. In addition to causing a rapid and sustained activation of eNOS by phosphorylation, polyphenols can increase the expression level of eNOS in endothelial cells leading to an increased formation of NO. Moreover, the polyphenol-induced endothelium-dependent relaxation also involves endothelium-derived hyperpolarizing factor, besides NO, in several types of arteries. Altogether, polyphenols have the capacity to improve the endothelial control of vascular tone not only in several experimental models of cardiovascular diseases such as hypertension but also in healthy and diseased humans. Thus, these experimental and clinical studies highlight the potential of polyphenol-rich sources to provide vascular protection in health and disease.

Renal hypouricemia (RHUC) is a hereditary disease that presents with increased renal urate clearance and hypouricemia due to genetic mutations in the urate transporter URAT1 or GLUT9 that reabsorbs urates in the renal proximal tubule. Exercise-induced acute kidney injury (EIAKI) is known to be a complication of renal hypouricemia. In the skeletal muscle of RHUC patients during exhaustive exercise, the decreased release of endothelial-derived hyperpolarization factor (EDHF) due to hypouricemia might cause the disturbance of exercise hyperemia, which might increase post-exercise urinary urate excretion. In the kidneys of RHUC patients after exhaustive exercise, an intraluminal high concentration of urates in the proximal straight tubule and/or thick ascending limb of Henle’s loop might stimulate the luminal Toll-like receptor 4–myeloid differentiation factor 88–phosphoinositide 3-kinase–mammalian target of rapamycin (luminal TLR4–MyD88–PI3K–mTOR) pathway to activate the nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome and may release interleukin-1β (IL-1β), which might cause the symptoms of EIAKI.

Women with polycystic ovary syndrome (PCOS) are often presented with hyperandrogenemia along with vascular dysfunction and elevated blood pressure. In animal models of PCOS, antiandrogen treatment decreased blood pressure, indicating a key role for androgens in the development of hypertension. However, the underlying androgen-mediated mechanism that contributes to increased blood pressure is not known. This study determined whether elevated androgens affect endothelium-derived hyperpolarizing factor (EDHF)-mediated vascular relaxation responses through alteration in function of gap junctional proteins. Female rats were implanted with placebo or dihydrotestosterone (DHT) pellets (7.5 mg, 90-day release). After 12 weeks of DHT exposure, blood pressure was assessed through carotid arterial catheter and endothelium-dependent mesenteric arterial EDHF relaxation using wire myograph. Connexin expression in mesenteric arteries was also examined. Elevated DHT significantly increased mean arterial pressure and decreased endothelium-dependent EDHF-mediated acetylcholine relaxation. Inhibition of Cx40 did not have any effect, while inhibition of Cx37 decreased EDHF relaxation to a similar magnitude in both controls and DHT females. On the other hand, inhibition of Cx43 significantly attenuated EDHF relaxation in mesenteric arteries of controls but not DHT females. Elevated DHT did not alter Cx37 or Cx40, but decreased Cx43 mRNA and protein levels in mesenteric arteries. In vitro exposure of DHT to cultured mesenteric artery smooth muscle cells dose-dependently downregulated Cx43 expression. In conclusion, increased blood pressure in hyperandrogenic females is due, at least in part, to decreased EDHF-mediated vascular relaxation responses. Decreased Cx43 expression and activity may play a role in contributing to androgen-induced decrease in EDHF function. Summary Sentence Hyperandrogenism in female rats reduced EDHF function via decrease in connexin 43 expression and activity in mesenteric arteries, providing a molecular mechanism linking elevated androgens and increased blood pressure.

Background and purpose: The small and intermediate conductance, Ca2+‐sensitive K+ channels (SKCa and IKCa, respectively) which are pivotal in the EDHF pathway may be differentially activated. The importance of caveolae in the functioning of IKCa and SKCa channels was investigated. Experimental approach: The effect of the caveolae‐disrupting agent methyl‐β‐cyclodextrin (MβCD) on IKCa and SKCa localization and function was determined. Key results: EDHF‐mediated, SKCa‐dependent myocyte hyperpolarizations evoked by acetylcholine in rat mesenteric arteries (following blockade of IKCa with TRAM‐34) were inhibited by MβCD. Hyperpolarizations evoked by direct SKCa channel activation (using NS309 in the presence of TRAM‐34) were also inhibited by MβCD, an effect reversed by cholesterol. In contrast, IKCa‐dependent hyperpolarizations (in the presence of apamin) were unaffected by MβCD. Similarly, in porcine coronary arteries, EDHF‐mediated, SKCa‐dependent (but not IKCa‐dependent) endothelial cell hyperpolarizations evoked by substance P were inhibited by MβCD. In mesenteric artery homogenates subjected to sucrose‐density centrifugation, caveolin‐1 and SK3 (SKCa) proteins but not IK1 (IKCa) protein migrated to the buoyant, caveolin‐rich fraction. MβCD pretreatment redistributed caveolin‐1 and SK3 proteins into more dense fractions. In immunofluorescence images of porcine coronary artery endothelium, SK3 (but not IK1) and caveolin‐1 were co‐localized. Furthermore, caveolin‐1 immunoprecipitates prepared from native porcine coronary artery endothelium contained SK3 but not IK1 protein. Conclusions and Implications: These data provide strong evidence that endothelial cell SKCa channels are located in caveolae while the IKCa channels reside in a different membrane compartment. These studies reveal cellular organisation as a further complexity in the EDHF pathway signalling cascade. British Journal of Pharmacology (2007) 151, 332–340; doi:10.1038/sj.bjp.0707222

The apamin‐sensitive small‐conductance Ca2+‐activated K+ channel (SKCa) was characterized in porcine coronary arteries. In intact arteries, 100 nM substance P and 600 μM 1‐ethyl‐2‐benzimidazolinone (1‐EBIO) produced endothelial cell hyperpolarizations (27.8±0.8 mV and 24.1±1.0 mV, respectively). Charybdotoxin (100 nM) abolished the 1‐EBIO response but substance P continued to induce a hyperpolarization (25.8±0.3 mV). In freshly‐isolated endothelial cells, outside‐out patch recordings revealed a unitary K+ conductance of 6.8±0.04 pS. The open‐probability was increased by Ca2+ and reduced by apamin (100 nM). Substance P activated an outward current under whole‐cell perforated‐patch conditions and a component of this current (38%) was inhibited by apamin. A second conductance of 2.7±0.03 pS inhibited by d‐tubocurarine was observed infrequently. Messenger RNA encoding the SK2 and SK3, but not the SK1, subunits of SKCa was detected by RT – PCR in samples of endothelium. Western blotting indicated that SK3 protein was abundant in samples of endothelium compared to whole arteries. SK2 protein was present in whole artery nuclear fractions. Immunofluorescent labelling confirmed that SK3 was highly expressed at the plasmalemma of endothelial cells and was not expressed in smooth muscle. SK2 was restricted to the peri‐nuclear regions of both endothelial and smooth muscle cells. In conclusion, the porcine coronary artery endothelium expresses an apamin‐sensitive SKCa containing the SK3 subunit. These channels are likely to confer all or part of the apamin‐sensitive component of the endothelium‐derived hyperpolarizing factor (EDHF) response. British Journal of Pharmacology (2002) 135, 1133–1143; doi:10.1038/sj.bjp.0704551

Robert Furchgott’s discovery of the obligatory role that the endothelium plays in the regulation of vascular tone has proved to be a major advance in terms of our understanding of the cellular basis of diabetic vascular disease. Endothelial dysfunction, as defined by a reduction in the vasodilatation response to an endothelium-dependent vasodilator (such as acetylcholine) or to flow-mediated vasodilatation, is an early indicator for the development of the micro- and macroangipathy that is associated with diabetes. In diabetes, hyperglycaemia plays a key role in the initiation and development of endothelial dysfunction; however, the cellular mechanisms involved as well as the importance of dyslipidaemia and co-morbidities such as hypertension and obesity remain incompletely understood. In this review, we discuss the mechanisms whereby hyperglycaemia, oxidative stress and dyslipidaemia can alter endothelial function and highlight their effects on endothelial nitric oxide synthase (eNOS), the endothelium-dependent hyperpolarising factor (EDHF) pathway(s), as well as on the role of endothelium-derived contracting factors (EDCFs) and adipocyte-derived vasoactive factors such as adipose-derived relaxing factor (ADRF).