Abstract
The role of vascular gap junctions in the conduction of intercellular Ca2+ and vasoconstriction along small resistance arteries is not entirely understood. Some depolarizing agents trigger conducted vasoconstriction while others only evoke a local depolarization. Here we use a novel technique to investigate the temporal and spatial relationship between intercellular Ca2+ signals generated by smooth muscle action potentials (APs) and vasoconstriction in mesenteric resistance arteries (MA). Pulses of exogenous KCl to depolarize the downstream end (T1) of a 3 mm long artery increased intracellular Ca2+ associated with vasoconstriction. The spatial spread and amplitude of both depended on the duration of the pulse, with only a restricted non-conducting vasoconstriction to a 1 s pulse. While blocking smooth muscle cell (SMC) K+ channels with TEA and activating L-type voltage-gated Ca2+ channels (VGCCs) with BayK 8644 spread was dramatically facilitated, so the 1 s pulse evoked intercellular Ca2+ waves and vasoconstriction that spread along an entire artery segment 3000 μm long. Ca2+ waves spread as nifedipine-sensitive Ca2+ spikes due to SMC action potentials, and evoked vasoconstriction. Both intercellular Ca2+ and vasoconstriction spread at circa 3 mm s−1 and were independent of the endothelium. The spread but not the generation of Ca2+ spikes was reversibly blocked by the gap junction inhibitor 18β-GA. Thus, smooth muscle gap junctions enable depolarization to spread along resistance arteries, and once regenerative Ca2+-based APs occur, spread along the entire length of an artery followed by widespread vasoconstriction.
Highlights
Cell-to-cell coupling via gap junctions provides a mechanistic basis for electrical coupling between vascular cells, such that depolarizing and hyperpolarizing electrical signals are able to spread along the vessel wall to coordinate myogenic responses [1,2,3,4,5,6,7]
The extent of current spread appears to vary depending on the cell type stimulated, so while the endothelium conducts a change in membrane potential over considerable distance, changes in smooth muscle membrane potential appear very restricted, at least in the small arteries of skeletal muscle [8,9,10]
We investigated the temporal and spatial relationship between propagating intercellular Ca2+ waves mediated by smooth muscle cell (SMC) action potentials (APs) and the ensuing vasoconstriction
Summary
Cell-to-cell coupling via gap junctions provides a mechanistic basis for electrical coupling between vascular cells, such that depolarizing and hyperpolarizing electrical signals are able to spread along the vessel wall to coordinate myogenic responses [1,2,3,4,5,6,7]. In the presence of TEA (5–10 mM), arterial SMCs have been shown to generate spike-like APs [14,15,16,17,18], sensitive to L-type VGCC blockers [17,18] It was not clear whether these Ca2+ -mediated APs can propagate via gap junctions to generate regenerative intercellular Ca2+ waves similar to those observed in visceral smooth muscles [19,20]. Cx40 is focussed in the endothelium, providing tight electrical coupling between these cells [32,33,34], and with SMCs through myoendothelial gap junctions [22,25,33,35,36] How these connexins influence intercellular communication through gap junctions and as such determine the ability of arteries to propagate vasoconstriction remains incomplete. We used a novel technique to allow the simultaneous measurement of Ca2+ and force at two ends of long isolated segments of resistance artery, showing that gap-junctions can allow the free movement of propagating vasoconstriction due to AP-mediated Ca2+ influx
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