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

Abstract

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 a single order of magnitude. Interestingly, however, intercellular response variation extended over 3 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 populationwide inputs, and enable robust noise filtering for efficient high-fidelity signaling.—Wilson, C., Saunter, C. D., Girkin, J. M., McCarron, J. G. Clusters of specialized detector cells provide sensitive and high fidelity receptor signaling in the intact endothelium.

The Endothelium Solves Problems That Endothelial Cells Do Not Know Exist

“…On activation an increase in Ca 2+ always occurred in the targeted cell. Propagation to additional cells occurred when multiple neighbouring cells were activated simultaneously [42]. These experiments establish that communication between neighbouring endothelial cells does occur and suggest that the endothelium is a network of interconnected cells.…”

“…Two main lines of experimental evidence suggest that the Ca 2+ rises in neighbouring cells are propagating signals, rather than independent Ca 2+ increases oscillating slightly out of phase with each other [42]. In the first, gap junction inhibitors, used to prevent communication among cells, blocked signal transmission [43].…”

“…In the first, gap junction inhibitors, used to prevent communication among cells, blocked signal transmission [43]. However, gap junction blockers (carbenoxolone, 18β-glycyrrhetinic acid, Gap27) have a broad spectrum of activity and many off-target effects that may inhibit Ca 2+ signals independently of effects on their putative target 29, 42, 44. In the second main line of evidence, photo-uncaging of caged IP 3 was used to activate specifically identified endothelial cells.…”

Communication of Ca2+ signals via tunneling membrane nanotubes is mediated by transmission of inositol trisphosphate through gap junctions

“…A similar mechanism may pertain to gap junction-coupled cells that are directly abutting (e.g. endothelial cells; [27]) if the connexins channels represent a substantial barrier to buffered diffusion of Ca 2+ . That is to say, although Ca 2+ is the ‘message’, IP 3 is the ‘messenger’.…”

Advancing Age Decreases Pressure-Sensitive Modulation of Calcium Signaling in the Endothelium of Intact and Pressurized Arteries

“…2a) [38]. The Ca 2+ response across the endothelium of arteries from aged animals was also heterogeneous (Fig.…”