Although the chemical nature of endothelium-derived hyperpolarizing factor (EDHF) remains elusive, electrophysiological evidence exists for electrical communication between smooth muscle cells and endothelial cells suggesting that electrotonic propagation of hyperpolarization may explain the failure to identify a single chemical factor as EDHF. Anatomical evidence for myoendothelial gap junctions, or the sites of electrical coupling, is, however, rare. In the present study, serial-section electron microscopy and reconstruction techniques have been used to examine the incidence of myoendothelial gap junctions in the proximal and distal mesenteric arteries of the rat where EDHF responses have been reported to vary. Myoendothelial gap junctions were found to be very small in the mesenteric arteries, the majority being <100 nm in diameter. In addition, they were significantly more common in the distal compared with the proximal regions of this arterial bed. Pentalaminar gap junctions between adjacent endothelial cells were much larger and were common in both proximal and distal mesenteric arteries. These latter junctions were frequently found near the myoendothelial gap junctions. These results provide the first evidence for the presence of sites for electrical communication between endothelial cells and smooth muscle cells in the mesenteric vascular bed. Furthermore, the relative incidence of these sites suggests that there may be a relationship between the activity of EDHF and the presence of myoendothelial gap junctions.
Abstract-The nature of the vasodilator endothelium-derived hyperpolarizing factor (EDHF) is controversial, putatively involving diffusible factors and/or electrotonic spread of hyperpolarization generated in the endothelium via myoendothelial gap junctions (MEGJs). In this study, we investigated the relationship between the existence of MEGJs, endothelial cell (EC) hyperpolarization, and EDHF-attributed smooth muscle cell (SMC) hyperpolarization in two different arteries: the rat mesenteric artery, where EDHF-mediated vasodilation is prominent, and the femoral artery, where there is no EDHF-dependent relaxation. In the rat mesenteric artery, stimulation of the endothelium with acetylcholine (ACh) evoked hyperpolarization of both ECs and SMCs, and characteristic pentalaminar MEGJs were found connecting the two cell layers. Key Words: endothelium-derived hyperpolarizing factor Ⅲ myoendothelial gap junctions Ⅲ endothelium Ⅲ smooth muscle Ⅲ electrical coupling T he endothelium plays a central role in the regulation of vascular tone. 1 The endothelium is capable of exerting a profound relaxing influence on the underlying smooth muscle, mediated by at least three different factors, depending on the vascular bed. These include nitric oxide (NO) and prostacyclin, both diffusible factors. [2][3][4][5][6] In addition, after blockade of NO and prostacyclin synthesis, stimulation of the endothelium is capable of evoking vascular smooth muscle relaxation that has been attributed to a third factor, endothelium-derived hyperpolarizing factor (EDHF). [7][8][9][10][11][12][13][14][15] The hallmark of the vasorelaxation attributed to EDHF is that it is accompanied by membrane hyperpolarization. Consensus regarding the nature of EDHF is lacking, with evidence suggesting the involvement of a diffusible factor(s) released from the endothelium in some vascular beds. 11,12,16,17 Others propose that the hyperpolarization generated in endothelial cells (ECs) is capable of spreading electrotonically to the underlying smooth muscle cells (SMCs), 18,19,21,23,25 most likely via myoendothelial gap junctions (MEGJs). 9,18,19,21,[23][24][25][26] Evidence to support the transfer of a small molecule (eg, cAMP) via MEGJs has also been presented. 20,22 Support for the MEGJ hypothesis has come from studies in which gap junctions have been pharmacologically blocked, either with peptide mimetics of connexin 43 (Cx43) [27][28][29][30] or with glycyrrhetinic acid derivatives. 13,26,[31][32][33] Although the former have been demonstrated to indeed reduce dye coupling between Cx-transfected cells, 34 the latter seem to have some nonspecific actions. [31][32][33]35 An alternative and complementary approach would be to study an artery that lacked an EDHF-dependent relaxation and to test for the existence of agonist-induced hyperpolarization in the ECs and for the presence of MEGJs. The femoral artery represents such a tissue because EDHF does not contribute to endothelium-dependent SMC relaxation in this vessel. 36,37 In the present study, this artery was ...
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