On the Ca ²⁺ elevation in vascular endothelial cells due to inositol trisphosphate-sensitive store receptor activation: a data-driven modeling approach

Agonist-induced Ca ²⁺ signalling is essential for the regulation of many vital functions in endothelial cells (ECs). A broad range of stimuli elevate the cytosolic Ca ²⁺ concentration by promoting a pathway mediated by inositol 1,4,5 trisphosphate (IP ₃ ) which causes Ca ²⁺ release from intracellular stores. Despite its importance, there are very few studies focusing on the quantification of such dynamics. Here, by using data from isolated ECs, we constructed and tested a minimalistic model that can be used for capturing the main features (averaged over a cell population) of the Ca ²⁺ response to different IP ₃ stimulation levels. A suitable description of Ca ²⁺ -regulatory function of inositol 1,4,5 trisphosphate receptors (IP ₃ Rs) is identified by comparing the different model variants against experimental mean population data. The same approach is used to numerically assess the relevance of cytosolic Ca ²⁺ buffering, as well as Ca ²⁺ store IP ₃ -sensitivity in the overall cell dynamics. The variability in the dynamics’ features observed across the population can be explained (at least in part) through variation of certain model parameters (such as buffering capacity or Ca ²⁺ store sensitivity to IP ₃ ). The results, in terms of experimental fitting and validation, support the proposed minimalistic model as a reference framework for the quantification of the EC Ca ²⁺ dynamics induced by IP ₃ Rs activation.