Research ArticleVASCULAR BIOLOGY

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

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Sci. Signal.  04 Jul 2017:
Vol. 10, Issue 486, eaal3806
DOI: 10.1126/scisignal.aal3806

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Ca2+, the intercellular signal in arterioles

Vasoconstriction must be balanced with vasodilation, particularly in the arterioles that supply tissues with blood. Endothelial cells protrude through holes in the internal elastic lamina in arterioles to make contact with vascular smooth muscle cells. Gap junctions are present at these sites where endothelial cells meet vascular smooth muscle cells. IP3 has been thought to be a signal that passes through these gap junctions to endothelial cells to mediate vasodilation. However, Garland et al. showed that it was Ca2+, rather than IP3, that entered vascular smooth muscle cells through voltage-gated Ca2+ channels, subsequently passed through gap junctions into endothelial cells, and initiated vasodilation mediated by endothelial cells. The magnitude of these Ca2+ signals in endothelial cells depended on IP3 receptors. These results resolve a long-standing controversy over how vascular smooth muscle cells communicate with endothelial cells to trigger feedback vasodilation.

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+ (IKCa) 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.

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