The single layer of cells lining all blood vessels, the endothelium, is a sophisticated coordination center that controls a wide range of vascular functions which include the regulation of blood pressure and blood flow via changes in vascular contractility. To coordinate vascular function, cell communication and interactions are required for tissue level responses to emerge. A significant form of cell-cell communication occurs by the propagation of Ca²⁺ signals between cells (‘Ca²⁺ waves’). We find that multiple mechanisms maintain communication so that Ca²⁺ wave propagation occurs irrespective of the status of cell connectivity. Between adjoining cells, g-protein coupled, regenerative IP₃-induced IP₃ production transmits Ca²⁺ signals and explains the propagated vasodilation that underlies the increased blood flow accompanying tissue activity. By controlling the production of IP₃, the inositide is itself sufficient to evoke a regenerative phospholipase C-dependent Ca²⁺ wave across coupled cells. None of gap junctions, Ca²⁺ diffusion or the release of extracellular messengers are required to support this type of intercellular Ca²⁺ signaling. In contrast, when a discontinuity between cells exists, ATP released as a diffusible extracellular messenger transmits Ca²⁺ signals and drives propagated vasodilation. These results show that self-reinforcing IP₃-induced IP­₃ production drives intercellular signalling and reveal how communication is maintained in the face of endothelial damage. The findings provide a new framework for understanding Ca²⁺ wave propagation and cell-cell signaling in the endothelium