Ca 2+ Influx Through Vascular Smooth Muscle Cell Voltage‐Gated Ca 2+ Channels Increases Endothelial Cell Ca 2+ to Evoke Vasodilation

Abstract

Global increases in vascular smooth muscle cell (SMC) intracellular Ca2+ typically lead to the formation of Ca2+-dependent cross-bridges between actin and myosin causing SMC contraction and vasoconstriction. We now show in skeletal muscle arterioles that Ca2+ influx through SMC voltage-gated Ca2+ channels (VGCCs) can activate a vasodilator signaling pathway in adjacent endothelial cells (ECs), so forming a bidirectional, voltage-dependent circuit between the SMCs and ECs, which provides negative feedback to supress vasoconstriction. Rat isolated cremaster arterioles from male Wistar rats were cannulated, pressurized and loaded with Oregon Green® 488 BAPTA-1 to image [Ca2+]i changes in either ECs and/or SMCs using laser scanning confocal microscopy. Direct activation of SMC VGCCs with BayK8644, or depolarization with raised K+, 4-AP or the α1-adrenoceptor agonist phenylephrine (PE), each indirectly stimulated local and propagating cell-wide Ca2+ events in the adjacent ECs. In freshly isolated EC tubes, which lack influence from SMCs, direct and indirect activators of VGCCs did not alter EC [Ca2+]i. These data demonstrate a SMC-EC circuit that links VGCC-dependent EC Ca2+ activity to feedback regulation of vascular tone. Selective block of EC Ca2+-activated K+ (KCa) channels markedly enhanced contraction to both direct (BayK8644) or indirect (PE) activators of VGCCs. Our data clearly demonstrate a link between global increases in SMC Ca2+ with a secondary increase in EC Ca2+ and activation of EC KCa channels, to provide EC-dependent feedback to supress vasoconstriction. This work was supported by the British Heart Foundation and the Wellcome Trust.