Abstract
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.
Highlights
The calcium ion is a universal second messenger mediating a wide range of dynamic cell functions, such as exocytosis, contraction, transcription, and proliferation [1,2,3]
As calcium is one of the most important second messengers, collective calcium signaling may serve as a broad mechanism in regulating various cell functions
To explore the effects of cellular architecture, histamine-induced calcium signaling was monitored in individual endothelial cells, monolayers, self-assembled capillary-like networks, and plasma lithography microengineered cell networks (Fig 1)
Summary
The calcium ion is a universal second messenger mediating a wide range of dynamic cell functions, such as exocytosis, contraction, transcription, and proliferation [1,2,3]. These biological processes that span time scales from microseconds to hours are regulated by diverse calcium signaling mechanisms. The calcium dynamics are regulated by multiple intracellular calcium processing mechanisms, such as non-selective cation channels, voltage-dependent calcium channels, store-operated calcium channels, calcium-induced calcium release, and phospholipase C mediated inositol 1,4,5-trisphosphate activity [3]. The effects of structural arrangement, as seen in diverse vascular structures, on calcium signaling and their functional implications are poorly understood
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