© 2000 American Heart Association, Inc.
Editorials |
A Case for Myoendothelial Gap Junctions
From the Department of Pharmacology, University of Vermont, Burlington, Vt.
Correspondence to Dr Mark Nelson, Room B-303, Given Building, Department of Pharmacology, University of Vermont, Burlington, VT 05404. E-mail nelson{at}salus.med.uvm.edu
Key Words: endothelium • smooth muscle • gap junctions
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Introduction |
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 Top Introduction References |
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Tissue perfusion is controlled by a network of resistance arteries linked in series and parallel with one another. It has been long appreciated that blood flow resistance is distributed throughout this network, and thus substantive change in perfusion only occurs when coupled arteries respond in a coordinated fashion. To coordinate vasomotor responses, vascular cells must communicate with one another. This communication is, in part, facilitated by gap junctions, which are intercellular pores that permit charged ions, second messenger molecules, and small metabolites to pass among adjacent cells. Gap junctions are formed by two hemichannels, each containing 6 connexin proteins. At present, the connexin gene family is comprised of 14 members, with the most predominant subtypes being Cx40 and Cx43 in vascular smooth muscle1 and Cx37, Cx40, and Cx43 in endothelial cells.2
For gap junctions to form an electrical or diffusional conduit, vascular cells must lie in close apposition to each other. With few structural elements limiting the contact of adjacent smooth muscle cells or adjacent endothelial cells, it has been widely accepted that these cells are homologously coupled. Indeed, studies using connexin antibodies to characterize gap junctional distribution have substantiated this view.1 3 4 In contrast, the internal elastic lamina, a connective tissue layer that separates smooth muscle from the endothelium, has been presumed to prevent the formation of heterologous (ie, myoendothelial) gap junctions. However, some studies have shown that the internal elastic lamina is not contiguous and that endothelial cells can indeed penetrate this barrier, emerging in close apposition to the smooth muscle cell layer.5 6 7 Such findings, coupled with observations indicating that fluorescent dyes can transfer between the two cell layers, suggest that myoendothelial gap junctions could indeed be present in the resistance vasculature.8 It is only the absence of connexin labeling that prevents definitive identification.
With structural studies pointing to the possibility of direct communication between endothelial and smooth muscle cells, questions have arisen as to whether function follows form. In general, the preferred method to functionally test for myoendothelial gap junctions has been to alter ion channel conductance in one cell type while monitoring membrane potential in the other cell type. Myoendothelial gap junctions are judged as being present or absent depending on the change in resting membrane potential. Although simple in theory, this approach necessitates the experimenter to identify the cell from which recordings are being obtained and ensure that the modulators of ion channel activity are cell selective. Indeed, it is because of the limited presentation of such controls that it has been difficult to conclusively resolve whether myoendothelial gap junctions are present in the resistance vasculature.
In this issue of Circulation Research, Emerson and Segal9 provide both structural and functional evidence for myoendothelial coupling in feed arteries isolated from the hamster retractor muscle. Electron photomicrographs (see Figure 19 ) show that endothelial cells come into close contact with the smooth muscle cell layer, a structural prerequisite for myoendothelial gap junctions. However, more impressive is the simultaneous recording of membrane potentials in an identified endothelial cell and a smooth muscle cell in a pressurized artery so as to provide functional evidence for myoendothelial gap junctions. By using two microelectrodes, the authors were able to inject positive and negative currents into one cell layer while monitoring the membrane potential response of the adjacent cell layer. It is with this approach that Emerson and Segal9 were able to demonstrate the spread of current not only along an artery but between the two cell layers, an observation consistent with myoendothelial gap junctions. What makes these data particularly compelling is the use of fluorescent dyes to identify the cells from which recordings have been obtained.
This study raises intriguing questions with respect to the function of myoendothelial gap junctions in integrated vascular behavior.9 Do these junctions, as suggested by authors, enable a change in endothelial K+ conductance to directly hyperpolarize and relax smooth muscle cells?9 Equally interesting, does smooth muscle hyperpolarization lead to a hyperpolarization of the adjacent endothelial cells, which in turn augment the release of hyperpolarizing and relaxing factors (eg, nitric oxide, prostaglandins, and cytochrome P-450 metabolites) from the endothelium? Such hypotheses are indeed provocative; however, they are difficult to resolve without a deeper understanding of the processes that regulate these pores. Indeed, far from being unregulated bidirectional pores, gap junctions display diverse properties, including asymmetric current-voltage behavior10 and intrinsic modulation by protein kinase C,11 cGMP,12 and Ca2+.13 By using an approach similar to that successfully used by Emerson and Segal,9 future studies will start to unravel the hidden secrets of gap junctional regulation.
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Footnotes |
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The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
See related article, pages 474–479
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References |
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TopIntroductionReferences |
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1. Li X, Simard JM. Multiple connexins form gap junction channels in rat basilar artery smooth muscle cells. Circ Res. 1999;84:1277–1284.
2.
Ko YS, Yeh HI, Rothery S, Dupont E, Coppen SR, Severs
NJ. Connexin make-up of endothelial gap junctions in
the rat pulmonary artery as revealed by immunoconfocal
microscopy and triple-label immunogold electron microscopy.
J Histochem Cytochem. 1999;47:683–692.
3. van Kempen MJ, Jongsma HJ. Distribution of connexin37, connexin40 and connexin43 in the aorta and coronary artery of several mammals. Histochem Cell Biol. 1999;112:479–486.[Medline] [Order article via Infotrieve]
4.
Yeh HI, Rothery S, Dupont E, Coppen SR, Severs
NJ. Individual gap junction plaques contain multiple connexins in
arterial endothelium. Circ Res. 1998;83:1248–1263.
5.
Sandow SL, Hill CE. Incidence of
myoendothelial gap junctions in the proximal and distal
mesenteric arteries of the rat is suggestive of a role in
endothelium-derived hyperpolarizing factor-mediated
responses. Circ Res. 2000;86:341–346.
6. Daut J, Standen NB, Nelson MT. The role of the membrane potential of endothelial and smooth muscle cells in the regulation of coronary blood flow. J Cardiovasc Electrophysiol. 1994;5:154–181.[Medline] [Order article via Infotrieve]
7.
Beny JL, Connat JL. An electron-microscopic study of
smooth muscle cell dye coupling in the pig coronary arteries:
role of gap junctions. Circ Res. 1992;70:49–55.
8.
Little TL, Xia J, Duling BR. Dye tracers define
differential endothelial and smooth muscle coupling
patterns within the arteriolar wall. Circ Res. 1995;76:498–504.
9.
Emerson GG, Segal SS. Electrical coupling between
endothelial cells and smooth muscle cells in hamster
feed arteries: role in vasomotor control. Circ Res. 2000;87:474–479.
10. Valiunas V, Weingart R, Brink PR. Formation of heterotypic gap junction channels by connexins 40 and 43. Circ Res. 2000;86:e42–e49.
11.
Lampe PD, TenBroek EM, Burt JM, Kurata WE, Johnson RG,
Lau AF. Phosphorylation of connexin43 on serine368 by
protein kinase C regulates gap junctional communication. J
Cell Biol. 2000;149:1503–1512.
12. Kwak BR, Saez JC, Wilders R, Chanson M, Fishman GI, Hertzberg EL, Spray DC, Jongsma HJ. Effects of cGMP-dependent phosphorylation on rat and human connexin43 gap junction channels. Pflügers Arch. 1995;430:770–778.
13.
Quist AP, Rhee SK, Lin H, Lal R.
Physiological role of gap-junctional hemichannels.
Extracellular calcium-dependent isosmotic volume regulation.
J Cell Biol.. 2000;148:1063–1074.
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