Intercellular communication controls agonist-induced calcium oscillations independently of gap junctions in smooth muscle cells

Abstract Agonist-induced calcium oscillations constitute a critical part of the machinery by which smooth muscle cells (SMCs) regulate constriction in airways and the vasculature. The frequency of these Ca2+ oscillations encodes the concentration of contractile agonist detected by the surface receptors on the SMC, with higher frequencies corresponding to higher agonist concentrations. Here, we report a collective phenomenon in SMCs where cells in multicellular ensembles exhibit synchronous agonist-induced Ca2+ oscillations and increased Ca2+ oscillation frequencies on stiffer substrates. This phenomenon is absent in isolated SMCs. We show that intercellular communication that enables this collective Ca2+ response in SMCs does not involve transport across gap junctions or extracellular diffusion of signaling molecules. Instead, our data support a model in which force-transfer among SMCs regulates their agonist response. This collective response could influence asthma and hypertension at an early stage and also cause the pathology to progress much faster than currently believed.