Biophysical characteristics of gap junctions in vascular wall cells: implications for vascular biology and disease

Brink, Peter R.; Ricotta, Joseph J.; Christ, George J.

doi:10.1590/s0100-879x2000000400007

Cited by 31 publications

(26 citation statements)

References 35 publications

(39 reference statements)

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confidence: 99%

“…The mechanistic basis for the observed and seemingly coordinated myogenic response, presumably via the propagation of myocyte depolarization and synchronization of constriction among individual myocytes, along the length of the artery is not fully understood. Our hypothesis is that one such possible mechanism is intercellular communication through gap junctions (4,7,14).Gap junctions are channels formed by the docking of two hemichannels across the extracellular space of adjacent myocytes. Each hemichannel is a hexameric structure of identical (homomeric) or nonidentical (heteromeric) gap junction proteins referred to as connexins.…”

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Inhibitors of gap junctions attenuate myogenic tone in cerebral arteries

Lagaud

Venkateswarlu

Knot

et al. 2002

American Journal of Physiology-Heart and Circulatory Physiology

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Lagaud, Guy, Venkateswarlu Karicheti, Harm. J. Knot, George J. Christ, and Ismail Laher. Inhibitors of gap junctions attenuate myogenic tone in cerebral arteries. Am J Physiol Heart Circ Physiol 283: H2177-H2186, 2002; 10.1152/ajpheart. 00605.2001.-The effects of two structurally distinct inhibitors of gap junction communication were studied by using three different forms of vasoconstriction in pressurized rat middle cerebral arteries. The sensitivity of myogenic tone (at 60 mmHg), vasopressin-induced tone (10 nM, at 20 mmHg), and depolarizing solution-induced tone (80 mM K ϩ , at 20 mmHg) to inhibition by heptanol (1.0 M to 3.0 mM) or 18␣-glycyrrhetinic acid (18␣-GA, 1.0 to 50 M) were determined. Pressure-induced myogenic tone was inhibited by heptanol (IC50 ϭ 0.75 Ϯ 0.09 mM) and 18␣-GA (ϳ30 M). Vasopressin-induced vasoconstriction was also inhibited by heptanol (IC 50 ϭ 0.4 Ϯ 0.3 mM) and 18␣-GA (Ͼ1 M). Depolarizing solution-induced vasoconstriction was less sensitive to inhibition by heptanol compared to vasopressin (P Ͻ 0.01) or pressure-induced constriction (P Ͻ 0.05). However, 18␣-GA did not inhibit depolarization-induced constriction. Sharp microelectrode experiments on isolated arteries revealed stable membrane potentials, with no detectable effect of heptanol (1 mM) or 18␣-GA (20-30 M) on the average membrane potential at 20 mmHg. However, Ϸ20% of impaled cells (5 of 28) exhibited uncharacteristic oscillations in membrane potential after pharmacological uncoupling. At 60 mmHg a Ϸ7-to 9-mV hyperpolarization and corresponding vasodilation (Ϸ50%) was observed, and the frequency of membrane potential oscillations doubled (9 of 23 cells). These data indicate that gap junctions play an important role in the maintenance and modulation of membrane potential and tone in cerebral resistance arteries.heptanol; glycyrrhetinic acid; vascular smooth muscle; resistance arteries; vasopressin and depolarization RESISTANCE ARTERIES react to increases and decreases in transmural pressure by constriction and dilation, respectively. This ability to respond to pressure in a manner independent of neurohormonal modulation (15) resides in vascular smooth muscle cells and was therefore termed a "myogenic response" (22). Currently, the mechanisms producing pressure-induced constriction are complex and not fully understood. However, elevations in pressure produce smooth muscle depolarization, which coincides with arterial constriction, and in some studies the production of spontaneous action potentials (20)(21)24). This in turn results in an inward movement of Ca 2ϩ via voltageoperated Ca 2ϩ channels. The net result of Ca 2ϩ influx (associated with membrane depolarization), coupled with enhanced myofilament calcium sensitivity, is an increase in vascular tone (15,24,28). Despite the stable arterial diameter commonly observed in small pressurized cerebral arteries, recent studies in resistance arteries demonstrate great individual variability in Ca 2ϩ -signaling modalities in individual myocytes within the vascular wall, suggesting...

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confidence: 99%

Inhibitors of gap junctions attenuate myogenic tone in cerebral arteries

Lagaud

Venkateswarlu

Knot

et al. 2002

American Journal of Physiology-Heart and Circulatory Physiology

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“…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 ).…”

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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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“…Myoendothelial gap junctions, connecting SMCs with ECs, are present in RMA [89,96], although they may be absent in some other vessels [138]. The homo-and hetero-cellular gap junctions are thought to be nonselective and permeable to ions, as well as to IP 3 molecules [82,95]. In this model all neighboring cells within the smooth muscle or the endothelial layer are connected via homocellular gap junctions while myoendothelial gap junctions connect overlapping EC and SMCs.…”

Section: Intercellular Communicationmentioning

confidence: 99%

“…The local Ca Gap junctions are believed to be nonselective in nature with similar permeability for all ions and IP 3 [82,95]. Literature values of R gj are spread over a large range of 70 -900 MΩ depending on the particular tissue and experimental conditions [96][97][98].…”

Section: Feedbackmentioning

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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Biophysical characteristics of gap junctions in vascular wall cells: implications for vascular biology and disease

Cited by 31 publications

References 35 publications

Inhibitors of gap junctions attenuate myogenic tone in cerebral arteries

Inhibitors of gap junctions attenuate myogenic tone in cerebral arteries

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

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

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