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Am J Physiol Heart Circ Physiol 291: H2036-H2038, 2006. First published July 28, 2006; doi:10.1152/ajpheart.00709.2006
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EDITORIAL FOCUS

Role of myoendothelial communication on arterial vasomotion

Jean-Louis Bény,1 Michèle Koenigsberger,2 and Roger Sauser2

1Department of Zoology and Animal Biology, University of Geneva, Geneva; and 2Laboratory of Cell Biophysics, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland

THE ARTERIAL SYSTEM secures an adequate supply of blood to organs. In many vessels, cyclic variations of the arterial diameter, a phenomenon called vasomotion, may contribute to the regulation of blood flow. Vasomotion is generated by synchronous oscillations in the cytosolic calcium concentration of adjacent smooth muscle cells (SMCs). Gap junctions mediating electrical and chemical couplings are probably involved in the synchronization process. In this context, two distinct information networks constitute the arterial wall: the intima, which is an endothelial cell (EC) layer, and the media, composed mainly of SMCs (2). The intima is in direct contact with the blood flow, and in situ studies in arterioles demonstrated the implication of ECs for coordination of vascular function (4, 5). Considered separately, the intima and the media are different in their ability to carry electrical information. SMCs are excitable fusiform cells running circularly around blood vessels, and in many arteries, they are only weakly coupled (7). In contrast with SMCs, ECs are aligned parallel to the longitudinal axis of the vessel so that one EC crosses ~20 SMCs (7). Moreover, the ECs are very well coupled by gap junctions (7). Changes in the membrane potential of an EC can then efficiently spread electrotonically along the artery, despite the fact that action potentials do not exist in most ECs (18). The endothelium is therefore a low-electrical-resistance pathway in comparison with the media (7). Exchange of electrical signal between the endothelium and the media is possible via myoendothelial gap junctions (21). It is now well established that ECs stimulated by an endothelium-dependent vasodilator are hyperpolarized (18). This hyperpolarization is electrotonically transmitted to the SMCs of the media, where it contributes to the vasodilatation by closing the voltage-dependent calcium channels. Changes in the membrane potential of SMCs are also transmitted to the ECs. The SMCs can be spontaneously electrically active, and stimulations of the receptors located on the SMCs causing vasodilatation or vasoconstriction are often associated with variations in the membrane potential of SMCs. Thus, during vasomotion, the calcium oscillations in individual SMCs could a priori be synchronized by homocellular electrical or chemical SMC-SMC coupling and/or via heterocellular coupling with ECs (16). The precise role of the endothelium and of its main derived factors, namely, nitric oxide (NO) and endothelium-derived hyperpolarizing factor (EDHF), in the generation and maintenance of vasomotion remains unclear (1, 9, 23). Some experimental studies claim that the presence of the endothelium is necessary for vasomotion (6, 11, 17, 19, 20). However, vasomotion is also observed in the absence of an intact endothelium (10, 15). In other studies, vasomotion is promoted when the endothelium is removed or when the NO synthase is inhibited (3, 16). The endothelium has also been shown to abolish vasomotion by desynchronizing calcium signals in SMCs (22). Note that such contradictory results are observed even for the same type of artery. For instance, the contradictory observations in Refs. 17, 20, and 22 have both been obtained on rat mesenteric arteries. Moreover, studies that agree about the necessity of the endothelium for vasomotion may disagree about whether NO or EDHF is required (17, 20).

Explanation for these contradictory experimental conclusions has been provided by a theoretical model (12–14). According to the model, the calcium dynamics in individual SMCs can be understood in terms of three different behaviors depending on the cytosolic free calcium concentration. At low and high calcium concentrations, the calcium is in a steady state and presents only asynchronous flashings and fluctuations arising from stochastic openings of membrane channels. At medium calcium concentrations, the calcium is in an oscillatory state. Assuming a homocellular metabolic coupling via gap junctions, the individual calcium oscillations may then synchronize and lead to vasomotion, independently of the presence of ECs. In terms of diameter variations, an increase in calcium concentration progressively leads to a light contraction, vasomotion, and finally a tonic contraction. These three behaviors have been previously observed experimentally using different agonist concentrations on endothelium-denuded rat mesenteric arteries (15). The model shows that the main effect of the endothelium-derived factors (NO and EDHF) is to decrease the mean calcium level in SMCs. As a consequence, the endothelium can give rise to vasomotion by inducing a transition from a steady state (with a high calcium level) to an oscillatory state (with a medium calcium level). On the other hand, the endothelium may abolish vasomotion by inducing a transition from an oscillatory regime (with a medium calcium level) to a steady state (with a low calcium level). These two possible types of transitions may then explain and reconcile the above-mentioned seemingly contradictory experimental observations about the role of the endothelium on vasomotion (Fig. 1). Indeed, the effect of the endothelium is always the same; only the initial state of the vessel (i.e., the initial calcium level) may be different. Note that the model does not take into consideration which endothelium-derived factor, NO or EDHF, influences most the cytosolic calcium of the SMCs. However, in small arteries (1–3 layers of SMCs), EDHF is likely to predominate, whereas in large arteries, NO is probably the dominant feature (2).


Figure 1
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  		Fig. 1. Proposed explanation for the seemingly contradictory experimental observations about the role of the endothelium on vasomotion. According to theoretical modelings of the calcium dynamics in a coupled population of smooth muscle cells (SMCs) and endothelial cells (ECs) (13), a variation in the mean cytosolic calcium level ([Ca2+]i) may induce transitions between nonoscillatory and oscillatory states. Increases in [Ca2+]i, and thus transitions from left to right, can be induced by an agonist stimulation or by inhibition of NO and/or EDHF. In contrast, production of NO and/or EDHF may result in transitions from right to left.

 
As reported in this issue of the American Journal of Physiology-Heart and Circulatory Physiology, Haddock et al. (8) have addressed the role of the endothelium in the coordination of SMCs leading to vasomotion. Haddock et al. (8) studied the membrane potential, diameter, and calcium dynamics in the primary branch of the rat basilar artery. They observed that SMCs of the cerebral vasculature generated spontaneous repetitive cytosolic calcium oscillations associated with membrane potential oscillations and vasomotion. Rhythmical depolarizations were present in both SMCs and ECs. Endothelial denudation led to a loss of coordinated rhythmical contractions and to a larger SMC input resistance. By inhibiting NO synthase with NG-nitro-L-arginine methyl ester in intact vessels and by mimicking its effect with cGMP in endothelium-denuded vessels, they concluded that NO plays only a modulatory role for vasomotion. Inhibition of EDHF with apamin and charybdotoxin resulted in a tonic contraction of the arteries independently of the integrity of the endothelium. Anatomical data confirmed the presence of extensive myoendothelial gap junctions comprised of connexin (Cx) 37 and Cx40. Cx37, Cx40, and Cx43 were expressed in ECs, whereas SMCs presented only Cx37. The gap junction uncouplers 37,43Gap27 and 40Gap27 hyperpolarized the artery and abolished the calcium oscillations in SMCs. The authors concluded that NO and EDHF are not essential to the synchronization of calcium oscillations among SMCs, in agreement with the theoretical modelings of vasomotion (13, 14). By suggesting that the endothelium is a low-resistance pathway that may be useful to coordinate the individual voltage changes in SMCs, the article of Haddock et al. (8) sheds light on an original role of the endothelium on vasomotion (Fig. 2).


Figure 2
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  		Fig. 2. In the present issue of the American Journal of Physiology-Heart and Circulatory Physiology, Haddock et al. (8) demonstrate an original role of the endothelium on vasomotion. Because the endothelium is an electrical lower resistance pathway by comparison to the coupled SMCs, when a SMC depolarizes, the electrical signal spreads through the endothelium to synchronize the neighboring SMCs.

 

ACKNOWLEDGMENTS

We thank Nicolas Roggli for drawing Fig. 2.

FOOTNOTES


Address for reprint requests and other correspondence: J.-L. Bény, Dept. of Zoology and Animal Biology, Univ. of Geneva, CH-1211 Geneva 4, Switzerland (jean-louis.beny{at}zoo.unige.ch)

REFERENCES

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