Electrical Coupling Between Endothelial Cells and Smooth Muscle Cells in Hamster Feed Arteries

Emerson, Geoffrey G.; Segal, Steven S.

doi:10.1161/01.res.87.6.474

Cited by 279 publications

(391 citation statements)

References 49 publications

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“…For example, in hamster retractor muscle arterioles, a more pronounced myoendothelial coupling was evident in acetylcholine-treated arteries than in arteries in which either smooth muscle or endothelial cells were stimulated by the injection of a negative current. 5 In the present study, we observed that the endothelial cell uncoupling observed 5 to 10 minutes after cell stimulation with either bradykinin or 11,12-EET was not detectable in cells pretreated with inhibitors of MEK, which prevent the activation of ERK1/2. Both bradykinin and 11,12-EET activated ERK1/2 in endothelial cells 30,31 and induced a MEK inhibitor-sensitive shift in the mobility of Cx43 in SDS-PAGE, changes that are indicative of Cx43 phosphorylation.…”

Section: Discussionsupporting

confidence: 41%

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Dynamic Modulation of Interendothelial Gap Junctional Communication by 11,12-Epoxyeicosatrienoic Acid

Popp

Brandes

Ott

et al. 2002

Circulation Research

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Abstract-Functional gap junctional communication between vascular cells has been implicated in ascending dilatation and the cytochrome P-450 (CYP) inhibitor-sensitive and NO-and prostacyclin-independent dilatation of many vascular beds. Here, we assessed the mechanisms by which the epoxyeicosatrienoic acids (EETs) generated by a CYP 2C enzyme control interendothelial gap junctional communication. In CYP 2C-expressing porcine coronary endothelial cells, bradykinin, which enhances EET formation, elicited a biphasic effect on the electrical coupling and transfer of Lucifer yellow between endothelial cells, consisting of a transient increase in coupling followed by a sustained uncoupling. The initial phase was sensitive to the CYP 2C9 inhibitor sulfaphenazole and the protein kinase A (PKA) inhibitors Rp-cAMPS and KT5720 and could be mimicked by forskolin and caged cAMP as well as by the PKA activators 5,6-dichloro-1-␤-D-ribofuranosylbenzimidazole 3Ј,5Ј-cyclic monophosphorothioate sodium salt and Sp-cAMPS. Gap junction uncoupling in bradykinin-stimulated porcine coronary endothelial cells was prevented by inhibiting the activation of extracellular signal-regulated kinase (ERK)1/2. In human endothelial cells, which express little CYP 2C, bradykinin elicited only an ERK1/2-mediated inhibition of intercellular communication. The CYP 2C9 product, 11,12-EET, also exerted a dual effect on the electrical and dye coupling of human endothelial cells, which was sensitive to PKA inhibition. These results demonstrate that an agonist-activated CYP-dependent pathway as well as 11,12-EET can positively regulate interendothelial gap junctional communication, most probably via the activation of PKA, an effect that is curtailed by the subsequent activation of ERK1/2. (Circ Res. 2002;90:800-806.)Key Words: connexin43 Ⅲ cytochrome P-450 2C Ⅲ cAMP Ⅲ endothelium-derived hyperpolarizing factors Ⅲ 11,12-epoxyeicosatrienoic acid I n large arteries and veins, gap junctions are known to be essential for the propagation of electrical signals between vascular smooth muscle cells, whereas in the microcirculation they appear to be involved in the phenomena of ascending dilation and endothelium-derived hyperpolarizing factor (EDHF)-mediated relaxation (see review 1 ).Myoendothelial gap junctions have been identified in numerous vascular beds, particularly in small arteries and terminal arterioles, 2 and it is assumed that the selective gating of such gap junctions plays an integral role in endotheliumdependent and in NO-and prostacyclin (PGI 2 )-independent relaxation. 3-6 However, there has been no convincing demonstration of a direct link between dynamic alterations in myoendothelial gap junctions and relaxation/vasodilatation.Interendothelial, rather than myoendothelial, cell communication has recently been proposed to be the pathway by which hyperpolarization and vasodilatation are conducted along agonist-stimulated resistance vessels. 7 In mice and hamsters, 8 -10 this phenomenon has been linked to a cytochrome P-450 (CYP)-dependent process t...

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Section: Discussionsupporting

confidence: 41%

“…[3][4][5][6] However, there has been no convincing demonstration of a direct link between dynamic alterations in myoendothelial gap junctions and relaxation/vasodilatation.…”

mentioning

confidence: 99%

Dynamic Modulation of Interendothelial Gap Junctional Communication by 11,12-Epoxyeicosatrienoic Acid

Popp

Brandes

Ott

et al. 2002

Circulation Research

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“…Stimulation of endothelial cells can also produce smooth muscle cell hyperpolarization through release of autacoids that activate K ϩ channels in smooth muscle (12). Furthermore, the conduction of vasodilation can attenuate sympathetic vasoconstriction (45), with hyperpolarization initiated and conducted along the endothelium and into the surrounding smooth muscle cells through myoendothelial gap junctions (23,78). These signaling pathways provide alternative mechanisms through which exerciseinduced increases in metabolites and blood flow can influence smooth muscle contraction.…”

Section: Mechanisms Underlying Functional Sympatholysismentioning

confidence: 99%

Neural control of muscle blood flow during exercise

Thomas¹,

Segal

2004

Journal of Applied Physiology

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220

174

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.-Activation of skeletal muscle fibers by somatic nerves results in vasodilation and functional hyperemia. Sympathetic nerve activity is integral to vasoconstriction and the maintenance of arterial blood pressure. Thus the interaction between somatic and sympathetic neuroeffector pathways underlies blood flow control to skeletal muscle during exercise. Muscle blood flow increases in proportion to the intensity of activity despite concomitant increases in sympathetic neural discharge to the active muscles, indicating a reduced responsiveness to sympathetic activation. However, increased sympathetic nerve activity can restrict blood flow to active muscles to maintain arterial blood pressure. In this brief review, we highlight recent advances in our understanding of the neural control of the circulation in exercising muscle by focusing on two main topics: 1) the role of motor unit recruitment and muscle fiber activation in generating vasodilator signals and 2) the nature of interaction between sympathetic vasoconstriction and functional vasodilation that occurs throughout the resistance network. Understanding how these control systems interact to govern muscle blood flow during exercise leads to a clear set of specific aims for future research.

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“…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]. Conduction studies have indicated that gap junctions between endothelial cells may be involved in the propagation of the EDHF response downstream along the vessel [14,15], and EDHF-attributed hyperpolarisations also propagate from endothelial cells through the entire smooth muscle layer via gap junctions, with a current that spreads with negligible attenuation [16].…”

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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Electrical Coupling Between Endothelial Cells and Smooth Muscle Cells in Hamster Feed Arteries

Cited by 279 publications

References 49 publications

Dynamic Modulation of Interendothelial Gap Junctional Communication by 11,12-Epoxyeicosatrienoic Acid

Dynamic Modulation of Interendothelial Gap Junctional Communication by 11,12-Epoxyeicosatrienoic Acid

Neural control of muscle blood flow during exercise

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

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