On the Ca2＋ elevation in vascular endothelial cells due to inositol trisphosphate-sensitive store receptors activation: A data-driven modeling approach

Abstract

Agonist-induced Ca2+ signaling is essential for the regulation of many vital functions in endothelial cells (ECs). A broad range of stimuli elevate the cytosolic Ca2＋ concentration by promoting a pathway mediated by inositol 1,4,5 trisphosphate (IP3) which causes Ca2＋ release from intracellular stores. Despite its importance, there are very few studies focusing on the quantification of such dynamics in the vascular endothelium. Here, by using data from isolated ECs, we established a minimalistic modeling framework able to quantitatively capture the main features (averaged over a cell population) of the cytosolic Ca2＋ response to different IP3 stimulation levels. A suitable description of Ca2＋-regulatory function of inositol 1,4,5 trisphosphate receptors (IP3Rs) and corresponding parameter space are identified by comparing the different model variants against experimental mean population data. The same approach is used to numerically assess the relevance of cytosolic Ca2＋ buffering, as well as Ca2＋ store IP3-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 Ca2＋ store sensitivity to IP3). The results, in terms of experimental fitting and validation, support the proposed minimalistic model as a reference framework for the quantification of the EC Ca2＋ dynamics induced by IP3Rs activation.