  The nucleotides ATP and ADP regulate many aspects of endothelial cell (EC)
biology, including intracellular calcium concentrations, focal adhesion
activation, cytoskeletal organization, and cellular motility. In vivo, ECs are
constantly under flow, and the concentration of ATP/ADP on the EC surface is
determined by the combined effects of nucleotide convective and diffusive
transport as well as hydrolysis by ectonucleotidases on the EC surface. In
addition, experiments have demonstrated that flow induces ATP release from the
cells. Previously computational models have incorporated the above effects and
thus described concentration at the EC surface. However, it remains unclear
what physical processes are responsible for nucleotide regulation. While some
EC responses to flow have been shown to be directly driven by shear stress,
others appear to also involve a non-negligible contribution of transport. In
the present work, we develop a mathematical model and perform numerical
simulations to investigate the relative contributions of shear stress and
transport to nucleotide concentration at the EC surface, with the effect of
cell density. Because in vitro experiments are performed by using confluent
cells in some cases and subconfluent cells in other cases, we also investigate
the effect of cell density on the results. The outcomes of the simulations
demonstrate a complex interplay between shear stress and transport such that
transport has a significant contribution at certain shear stress values but not
at others. The effect of transport on nucleotide concentration increases with
cell density. The present findings enhance our understanding of the mechanisms
that govern the regulation of such molecules at the EC surface under flow. The
implications of these findings for downstream responses such as cellular
motility merit future investigation.
