Garland Christopher J, Bagher Pooneh, Powell Chloe, Ye Xi, Lemmey Hamish A L, Borysova Lyudmyla, Dora Kim A
Department of Pharmacology, University of Oxford, Mansfield Road, Oxford OX1 3QT, UK.
Sci Signal. 2017 Jul 4;10(486):eaal3806. doi: 10.1126/scisignal.aal3806.
Vascular smooth muscle contraction is suppressed by feedback dilation mediated by the endothelium. In skeletal muscle arterioles, this feedback can be activated by Ca 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 Ca or inositol trisphosphate (IP) may provide the intercellular signal, it is generally thought that IP diffusion is responsible. We provide evidence that Ca entry through L-type voltage-dependent Ca 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 Ca signaling. In endothelial cells in which IP receptors (IPRs) were blocked, VDCC-driven Ca 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 IPRs were not blocked, VDCC-driven Ca events in endothelial cells were amplified to form propagating waves. These waves activated voltage-insensitive, intermediate-conductance, Ca-activated K (IK) 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 Ca to endothelial cells to activate a feedback circuit that protects tissue blood flow.
血管平滑肌收缩受到内皮介导的反馈性舒张的抑制。在骨骼肌小动脉中，这种反馈可由钙离子信号从平滑肌通过缝隙连接传递至内皮细胞而激活，内皮细胞穿过内弹性膜上的小孔伸出并与血管平滑肌细胞接触。尽管理论上钙离子或肌醇三磷酸（IP）都可能提供细胞间信号，但一般认为是IP的扩散起作用。我们提供的证据表明，血管平滑肌中通过L型电压依赖性钙通道（VDCCs）进入的钙离子能够通过与内弹性膜上小孔对齐的位置传递至内皮细胞，其数量足以激活内皮细胞的钙离子信号。在IP受体（IPRs）被阻断的内皮细胞中，由VDCC驱动的钙离子事件是短暂的，且局限于穿过内弹性膜与血管平滑肌细胞接触的内皮细胞。在IPRs未被阻断的内皮细胞中，内皮细胞中由VDCC驱动的钙离子事件会被放大形成传播波。这些波激活了电压不敏感、中等电导、钙激活钾（IK）通道，从而提供了有效地抑制血管收缩并实现称为血管运动的收缩和舒张循环的反馈。因此，刺激血管平滑肌去极化的激动剂会为内皮细胞提供钙离子以激活一个保护组织血流的反馈回路。
