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PLoS Comput Biol. 2016 May 19;12(5):e1004955. doi: 10.1371/journal.pcbi.1004955. eCollection 2016 May.

Cellular Architecture Regulates Collective Calcium Signaling and Cell Contractility.

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Department of Mechanical Science and Engineering, University of Illinois at Urbana-Champaign, Urbana, Illinois, United States of America.
Department of Aerospace and Mechanical Engineering, The University of Arizona, Tucson, Arizona, United States of America.
Cardiovascular Innovation Institute, University of Louisville & Jewish Hospital, Louisville, Kentucky, United States of America.
Material Science and Engineering Department, The University of Arizona, Tucson, Arizona, United States of America.
Department of Pharmacology and Toxicology, The University of Arizona, Tucson, Arizona, United States of America.
Departments of Biomedical Engineering, Mechanical Engineering, and Surgery, The Pennsylvania State University, University Park, Pennsylvania, United States of America.


A key feature of multicellular systems is the ability of cells to function collectively in response to external stimuli. However, the mechanisms of intercellular cell signaling and their functional implications in diverse vascular structures are poorly understood. Using a combination of computational modeling and plasma lithography micropatterning, we investigate the roles of structural arrangement of endothelial cells in collective calcium signaling and cell contractility. Under histamine stimulation, endothelial cells in self-assembled and microengineered networks, but not individual cells and monolayers, exhibit calcium oscillations. Micropatterning, pharmacological inhibition, and computational modeling reveal that the calcium oscillation depends on the number of neighboring cells coupled via gap junctional intercellular communication, providing a mechanistic basis of the architecture-dependent calcium signaling. Furthermore, the calcium oscillation attenuates the histamine-induced cytoskeletal reorganization and cell contraction, resulting in differential cell responses in an architecture-dependent manner. Taken together, our results suggest that endothelial cells can sense and respond to chemical stimuli according to the vascular architecture via collective calcium signaling.

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