A MATHEMATICAL-MODEL OF THE CYTOSOLIC-FREE CALCIUM RESPONSE IN ENDOTHELIAL-CELLS TO FLUID SHEAR-STRESS

Important among the responses of endothelial cells to flow stimuli are cytosolic-free calcium transients. These transients are mediated by s everal factors, including blood-borne agonists, extracellular calcium, and fluid-imposed shear forces. A mathematical model has been develop ed describing the recognition and transduction of shear stress to the second messenger cytosolic calcium. Shear stress modulates the calcium response via at least two modalities. First, mass transfer of agonist to the cell surface is enhanced by perfusion and is thus related to s hear stress. Second, the permeability of the cell membrane to extracel lular calcium increases upon exposure to shear stress. A mass balance for agonist in the perfusate is coupled to a previously published calc ium dynamics model. Computations indicate a flow region where the tran sient moves from transport limited to kinetically limited. Parametric studies indicate distinct contributions to the time course by each ste p in the process. These steps include the time to develop the concentr ation boundary layer of agonist, receptor activation, and the mobiliza tion of calcium from intracellular stores. Exogenous calcium is presum ed to enter the cell via shear stress-gated ion channels. The model pr edicts a sigmoidal dependence of calcium influx upon shear stress. The peak value of the transient is determined largely by the agonist path way, whereas the plateau level is governed by calcium influx. The mode l predicts the modulation of the calcium transient in the physiologica lly relevant range of flow and the associated shear stress. This impli es that hemodynamics is important in regulating endothelial biology.