Voltage-dependent Ca2+ entry into smooth muscle during contraction promotes endothelium-mediated feedback vasodilation in arterioles

Abstract

Vascular smooth muscle contraction is suppressed by feedback dilation mediated by the endothelium. In skeletal muscle arterioles, this feedback can be activated by Ca²⁺ signals passing from smooth muscle through gap junctions to endothelial cells, which protrude through holes in the internal elastic lamina to make contact with vascular smooth muscle cells. Although hypothetically either Ca²⁺ or inositol trisphosphate (IP₃) may provide the intercellular signal, it is generally thought that IP₃ diffusion is responsible. We provide evidence that Ca²⁺ entry through L-type voltage-dependent Ca²⁺ channels (VDCCs) in vascular smooth muscle can pass to the endothelium through positions aligned with holes in the internal elastic lamina in amounts sufficient to activate endothelial cell Ca²⁺ signaling. In endothelial cells in which IP₃ receptors (IP₃Rs) were blocked, VDCC-driven Ca²⁺ events were transient and localized to the endothelium that protrudes through the internal elastic lamina to contact vascular smooth muscle cells. In endothelial cells in which IP₃Rs were not blocked, VDCC-driven Ca²⁺ events in endothelial cells were amplified to form propagating waves. These waves activated voltage-insensitive, intermediate-conductance, Ca²⁺-activated K⁺ (IK_Ca) channels, thereby providing feedback that effectively suppressed vasoconstriction and enabled cycles of constriction and dilation called vasomotion. Thus, agonists that stimulate vascular smooth muscle depolarization provide Ca²⁺ to endothelial cells to activate a feedback circuit that protects tissue blood flow.