ATP Release by Red Blood Cells under Flow: Model and Simulations

Results are encouraging

ATP is a major player as a signaling molecule in blood microcirculation. It is released by red blood cells (RBCs) when they are subjected to shear stresses large enough to induce a sufficient shape deformation. This prominent feature of chemical response to shear stress and RBC deformation constitutes an important link between vessel geometry, flow conditions, and the mechanical properties of RBCs, which are all contributing factors affecting the chemical signals in the process of vasomotor modulation of the precapillary vessel networks. Several in vitro experiments have reported on ATP release by RBCs due to mechanical stress. These studies have considered both intact RBCs as well as cells within which suspected pathways of ATP release have been inhibited. This has provided profound insights to help elucidate the basic governing key elements, yet how the ATP release process takes place in the (intermediate) microcirculation zone is not well understood. We propose here an analytical model of ATP release. The ATP concentration is coupled in a consistent way to RBC dynamics. The release of ATP, or the lack thereof, is assumed to depend on both the local shear stress and the shape change of the membrane. The full chemomechanical coupling problem is written in a lattice-Boltzmann formulation and solved numerically in different geometries (straight channels and bifurcations mimicking vessel networks) and under two kinds of imposed flows (shear and Poiseuille flows). Our model remarkably reproduces existing experimental results. It also pinpoints the major contribution of ATP release when cells traverse network bifurcations. This study may aid in further identifying the interplay between mechanical properties and chemical signaling processes involved in blood microcirculation.

A positive result

In this work, we have proposed a model for ATP release from RBCs and have explored it numerically. We have addressed the question of how geometry and stress amplitude in precapillary networks affect the ATP release from RBCs. With the help of experimental data, numerical simulations, and assumptions on molecular mechanisms, we were able to fix the model and its parameter values that generate results that semiquantitatively match existing in vitro shear experiments. In this model, the mechanical properties are mainly represented by membrane shear stress and curvature change (as an indicator of deformation level). At the molecular level, the Px1 hemichannel is considered as a main player of ATP release thanks to its sensitivity to shear stress level.

When the cell deforms significantly, another mechanism becomes possible, in which free actin is detached (because of high deformation) from cytoskeletal defects, which in turn activate the CFTR protein. The latter then upregulates Px1 to promote ATP release. Interestingly enough, despite the oversimplification of the model—using only a Heaviside step function (for shear stress sensing) and a bounded linear function (for deformation sensing)—the model remarkably captures the essential pattern of ATP release reported in in vitro shear experiments.

A lattice-Boltzmann-based numerical solver coupling vesicle dynamics and solute advection-diffusion with arbitrary moving boundary conditions has been developed.

This solver is straightforwardly applicable to more detailed models in the future, including multicellular systems in complex geometry.

Biophysical Journal 115, 2218–2229, December 4, 2018 2229

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