John G. McCarron

Background and Purpose The single layer of cells lining all blood vessels, the endothelium, is a sophisticated signal co‐ordination centre that controls a wide range of vascular functions including the regulation of blood pressure and blood flow. To co‐ordinate activities, communication among cells is required for tissue level responses to emerge. While a significant form of communication occurs by the propagation of signals between cells, the mechanism of propagation in the intact endothelium is unresolved. Experimental Approach Precision signal generation and targeted cellular manipulation was used in conjunction with high spatiotemporal mesoscale Ca 2+ imaging in the endothelium of intact blood vessels. Key Results Multiple mechanisms maintain communication so that Ca 2+ wave propagation occurs irrespective of the status of connectivity among cells. Between adjoining cells, regenerative IP 3 ‐induced IP 3 production transmits Ca 2+ signals and explains the propagated vasodilation that underlies the increased blood flow accompanying tissue activity. The inositide is itself sufficient to evoke regenerative phospholipase C‐dependent Ca 2+ waves across coupled cells. None of gap junctions, Ca 2+ diffusion or the release of extracellular messengers is required to support this type of intercellular Ca 2+ signalling. In contrast, when discontinuities exist between cells, ATP released as a diffusible extracellular messenger transmits Ca 2+ signals across the discontinuity and drives propagated vasodilation. Conclusion and Implications These results show that signalling switches underlie endothelial cell‐to‐cell signal transmission and reveal how communication is maintained in the face of endothelial damage. The findings provide a new framework for understanding wave propagation and cell signalling in the endothelium.