Clusters of specialized detector cells provide sensitive and high fidelity receptor signaling in intact endothelium

Wilson, Calum and Saunter, Christopher D. and Girkin, John M. and McCarron, John G. (2016) Clusters of specialized detector cells provide sensitive and high fidelity receptor signaling in intact endothelium. FASEB Journal, 30 (5). pp. 2000-2013. ISSN 0892-6638 (

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Agonist-mediated signaling by the endothelium controls virtually all vascular functions. Because of the large diversity of agonists, each with varying concentrations, background noise often obscures individual cellular signals. How the endothelium distinguishes low-level fluctuations from noise, and decodes and integrates physiologically relevant information remains unclear. Here, we recorded changes in intracellular Ca2+ concentrations in response to acetylcholine in areas encompassing hundreds of endothelial cells from inside intact pressurized arteries. Individual cells responded to acetylcholine with a concentration-dependent increase in Ca2+ signals spanning one order of magnitude. Interestingly however, intercellular response variation extended over three orders of magnitude of agonist concentration, thus crucially enhancing the collective bandwidth of endothelial responses to agonists. We also show the accuracy of this collective mode of detection is facilitated by spatially-restricted clusters of comparably-sensitive cells arising from heterogeneous receptor expression. Simultaneous stimulation of clusters triggered Ca2+ signals that were transmitted to neighboring cells in a manner that scaled with agonist concentration. Thus, the endothelium detects agonists by acting as a distributed sensing system. Specialized clusters of detector cells, analogous to relay nodes in modern communication networks, integrate population-wide inputs and enable robust noise filtering for efficient high-fidelity signaling.