Evidence for the involvement of myoendothelial gap junctions in EDHF-mediated relaxation in the rat middle cerebral artery

Sokoya, Elke M.; Burns, Alan R.; Setiawan, Christopher Tan; Coleman, Harold A.; Parkington, Helena C.; Tare, Marianne

doi:10.1152/ajpheart.01047.2005

Cited by 43 publications

(54 citation statements)

References 41 publications

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confidence: 82%

“…Morphologically, myoendothelial gap junctions were visualized, 15,16 and specifically Cx40 and Cx37 have been located in myoendothelial gap junctions in rat cerebral vessels. 17,18 Functional experiments verified dye transfer and spreading of hyperpolarization from the endothelium into the smooth muscle, which suggests effective heterocellular coupling. 19 -22 Although in many experiments nonspecific blockade of gap junctions effectively abrogated EDHF-type dilations, this does not provide compelling evidence, because such blockers also affect ion channels and interrupt homocellular coupling within the endothelium and the smooth muscle layer, the latter being specifically important in larger vessels.…”

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confidence: 82%

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Distinct Endothelium-Derived Hyperpolarizing Factors Emerge In Vitro and In Vivo and Are Mediated in Part via Connexin 40–Dependent Myoendothelial Coupling

Boettcher

Wit

2011

Hypertension

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Abstract-The endothelium-derived hyperpolarizing factor (EDHF) contributes critically to the regulation of vascular tone.Its dependency on direct signaling through myoendothelial gap junctions composed of connexins (Cx) is controversially discussed. We studied the impact of Cx40 in EDHF-type dilations in vivo and in vitro (wire and pressure myography) in small arteries (A. gracilis) using different Cx40-deficient mouse models. Acetylcholine induced prominent EDHF-type dilations (inhibition of NO synthase and cyclooxygenase) of Ϸ90% (maximum effect) in wild-type and Cx40-deficient vessels (Cx40) in vitro under isobaric conditions. In contrast, under isometric conditions, EDHF-type relaxations were nearly abrogated in Cx40 Ϫ/Ϫ (9Ϯ3%) but only slightly reduced in wild-type vessels (45Ϯ4%; PϽ0.05). Vessels expressing Cx45 instead of Cx40 exhibited similarly reduced relaxations (13Ϯ1%), demonstrating that Cx45 cannot replace Cx40 functionally. The necessity of Cx40 in EDHF-type dilations under isometric conditions was verified by the attenuation in vessels being specifically deficient for Cx40 in endothelial cells (Cx40 fl :TIE2-Cre: 17Ϯ3%; Cx40-floxed controls: 67Ϯ6%; PϽ0.05). Nevertheless, EDHF-type dilations were Cx40 independent when studied isobarically. The EDHF-type dilation in vivo resembled the isobaric situation, being virtually Cx40 independent and similar powerful. Distinct EDHF mechanisms can be distinguished by their Cx40 dependency. A powerful EDHF is present in vivo and in vitro under isobaric conditions but is lacking in wire myography (isometric conditions). Herein, a less potent EDHF depends on Cx40 and may represent signaling through myoendothelial gap junctions. We suggest that distinct EDHFs (even in the same artery) explain partially the controversy on the role of myoendothelial gap junctions in EDHF signaling. (Hypertension. 2011;57:802-808.) • Online Data Supplement Key Words: myoendothelial coupling Ⅲ gap junctions Ⅲ connexins Ⅲ microcirculation Ⅲ endothelium-derived hyperpolarizing factor T he endothelium is the key player in arteries to control the contractile state of the adjacent smooth muscle and thereby vascular diameter. This function is achieved by the release of NO, prostaglandins, and the endothelium-derived hyperpolarizing factor (EDHF). Of these autocaids, NO predominates in large conducting arteries, whereas the importance of EDHF increases as the size of the arteries decreases. 1-5 NO and prostaglandins are well characterized with respect to chemistry and signaling cascades, but the nature of EDHF is controversially discussed. 6 -8 By definition, EDHF-type dilations are associated with smooth muscle hyperpolarization, which is followed by its relaxation, most likely through decreasing the open probability of voltagedependent L-type Ca 2ϩ -channels. Because EDHF-type dilations require an endothelial hyperpolarization through activation of Ca 2ϩ -activated K ϩ -channels (K Ca ) 9 -11 as an initial step the smooth muscle hyperpolarization may be caused by a direct charge transfer ...

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confidence: 82%

Distinct Endothelium-Derived Hyperpolarizing Factors Emerge In Vitro and In Vivo and Are Mediated in Part via Connexin 40–Dependent Myoendothelial Coupling

Boettcher

Wit

2011

Hypertension

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“…In addition to the involvement of K Ca channels, evidence exists for a role for intercellular pathways provided by gap junctions [10][11][12]. Gap junctions are formed by the docking of two connexin subunits, each made up of six connexin proteins arranged around a central core [13], which creates a channel allowing the direct exchange of ions and lowmolecular-weight molecules [13].…”

Section: Introductionmentioning

confidence: 99%

Reduced EDHF responses and connexin activity in mesenteric arteries from the insulin-resistant obese Zucker rat

et al. 2008

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Aims/hypothesis The objective of this study was to examine the effect of insulin resistance on endothelium-derived hyperpolarising factor (EDHF) and small mesenteric artery endothelial function using 25-week-old insulin-resistant obese Zucker rats (OZRs) and lean littermate control rats (LZRs). The involvement of gap junctions and their connexin subunits in the EDHF relaxation response was also assessed. Methods Mesenteric arteries were evaluated using the following assays: (1) endothelial function by pressure myography, with internal diameter recorded using video microscopy; (2) connexin protein levels by western blotting; and (3) Cx mRNA expression by real-time PCR. Results Relaxations in response to acetylcholine were significantly smaller in mesenteric arteries from the OZRs than the LZRs, whereas there was no difference in relaxations in response to levcromakalim. Responses to acetylcholine were not altered by nitric oxide inhibitors, but were abolished by charybdotoxin in combination with apamin, which blocked the EDHF component of the response. 40 Gap27 significantly attenuated the response to acetylcholine in the LZRs, but had no effect in the OZRs. Connexin 40 protein and Cx40 mRNA levels in mesenteric vascular homogenates were significantly smaller in the OZRs than in the LZRs, with no difference in connexin 43 or Cx43 mRNA levels. Conclusions/interpretation These findings demonstrate that endothelial dysfunction in mesenteric arteries from the insulin-resistant OZRs can be attributed to a defect in EDHF. The results also suggest that the defective EDHF is at least partly related to an impairment of connexin 40-associated gap junctions, through a decrease in connexin 40 protein and Cx40 mRNA expression in the OZRs.

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“…Many studies have supported MEGJs as being EDHF [88][89][90][91]116] although in some arterial beds, hyperpolarization is transferred from EC to SMC even in the presence of gap junction uncouplers like 18GA [93] . MEGJs provide a low resistance pathway for ionic communication between the two cell types.…”

Section: Role Of Myoendothelial Gap Junctionsmentioning

confidence: 99%

“…Electrical change measurements and dye transfer studies have established the ability of these junctions to transfer electrical and ionic changes between the two cell types along with the transport of small second messenger molecules such as IP 3 [84][85][86]. There is now a sizeable amount of evidence that EDHF is simply the electrotonic spread of hyperpolarization from EC to SMC via gap junctions [88][89][90][91]116]. MEGJ expression has been shown to increase with decrease in vessel size which is coincidental with regards to EDHF action [89].…”

Section: Introductionmentioning

confidence: 99%

Theoretical Investigations of Communication in the Microcirculation: Conducted Responses, Myoendothelial Projections and Endothelium Derived Hyperpolarizing Factor

Nagaraja¹

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This dissertation, written by Sridevi Nagaraja, and entitled Theoretical investigations of intercellular communication in the microcirculation: conducted responses, myoendothelial projections and endothelium derived hyperpolarizing factor, having been approved in respect to style and intellectual content, is referred to you for judgment.We have read this dissertation and recommend that it be approved. _______________________________________Wei-Chiang Lin dynamics in vascular cells in single as well as multicellular models. Advancement of these models is necessary to achieve the level of sophistication analogous to cardiac models. These models will contribute towards the development of a theoretical framework for the understanding of microcirculatory phenomena. It is also one of the most thoroughly studied vascular beds with vast amount of experimental data available. Therefore, in most of our models we use data from small rat mesenteric arteries (RMAs). This section describes the major channels and pumps present within the cytosol in the longitudinal direction of the cell.Through this process, it has become obvious that detailed models of Ca is still a need to build upon previous modeling work in order to develop cellular models that will assist in the investigations of vascular tone regulation in health and disease. Other channels specific to EC are described below. Inward rectifier potassium channelsInward rectifier potassium channels (K ir ) are sensitive to extracellular concentration of potassium in the range of 1 to 20 mM. These channels increase entry of potassium into the cell thereby hyperpolarizing of EC and subsequently the SMC. They are present in almost all endothelial cells and contribute towards the resting V m of the EC. EC K ir channels are known to be activated not only by potassium but also by shear stress. Theoretical modeling of vascular ECsThe first endothelial cell models were based on earlier generic models of Ca Endothelium derived controllers Nitric oxideNitric oxide was identified as the endothelium derived relaxing factor in 1980 ProstacyclinProstacyclin (PGI2) in rat mesenteric arterioles, PGI2 does not exert a hyperpolarizing effect. The involvement of PGI2 pathways is usually studied using COX inhibitor (Indomethacin). Endothelium derived hyperpolarizing factorEDHF is an endothelium derived non-nitric oxide (NO) and non-cyclicoxygenase and EC hyperpolarization by activation of IK Ca and SK Ca is now a widely accepted finger print of EDHF action across many studies.However, its propagation to the SMC is still being investigated. Myoendothelial feedbackStudies have shown that endothelium derived pathways can also be induced during SMC stimulation which brought about the concept of myoendothelial feedback. where R gj is gap junction resistance, and ∆V gj represents V m cells n-th and m-th ( Figure 2.2). where P gj,S is the gap junction permeability to S (e.g., Ca rectification is low at physiological concentration gradients, and a simpler linear approximation can ...

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Evidence for the involvement of myoendothelial gap junctions in EDHF-mediated relaxation in the rat middle cerebral artery

Cited by 43 publications

References 41 publications

Distinct Endothelium-Derived Hyperpolarizing Factors Emerge In Vitro and In Vivo and Are Mediated in Part via Connexin 40–Dependent Myoendothelial Coupling

Distinct Endothelium-Derived Hyperpolarizing Factors Emerge In Vitro and In Vivo and Are Mediated in Part via Connexin 40–Dependent Myoendothelial Coupling

Reduced EDHF responses and connexin activity in mesenteric arteries from the insulin-resistant obese Zucker rat

Theoretical Investigations of Communication in the Microcirculation: Conducted Responses, Myoendothelial Projections and Endothelium Derived Hyperpolarizing Factor

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