Although red blood cells (RBCs) are often described as oxygen carriers, their real function goes far beyond this simplistic image. RBCs also transport numerous macromolecules, the most emblematic of which is ATP, the major source of energy in the organism. ATP is released by RBCs under shear stress and reacts with the inner vascular wall (lined with endothelial cells), inducing a release of calcium (stored in the endothelial cells), which then produces nitric oxide, a vasodilator. A reduction in ATP release by RBCs is associated with diseases such as type II diabetes and cystic fibrosis. A priori, one might think that increasing hematocrit would be accompanied by an increase in the concentration of ATP in blood plasma. However, a maximum of ATP release requires a particular hematocrit, above or below which the release of ATP by RBCs falls. This conclusion was made possible by a detailed study of the different mechanisms involved including the interactions of RBCs with each other and with the vascular walls, permanent deformations in RBCs, and the conformational changes of protein channels regulating ATP release.
The cover image of the November 2 issue of Biophysical Journal is an artistic rendering of RBCs releasing ATP due to the hydrodynamic stress of blood flow. The RBCs are represented by red balloons in the blood vessel. The yellow color represents regions of RBC membrane (a membrane zoom is schematized in the lower image) with high shear stress, where ATP is released by protein channels denoted by violet tubes. The blue dots represent ATP molecules. RBCs in the center of the vessel experience a lower shear stress than those in the periphery and thus release a smaller amount of ATP than peripheral cells. ATP release is described by a stepwise function of shear stress. For a small hematocrit, cells are centered in the vessel and release a small amount of ATP per cell (due to the small shear stress there). When the hematocrit is large enough, a fraction of cells is expelled toward the periphery where shear stress is large, giving rise to a higher amount of ATP release per cell. On further increase of hematocrit, cell-cell interaction in the crowded suspension screens out the shear stress felt by each cell. Consequently, the ATP release per cell undergoes a decrease. This leads to the existence of a critical hematocrit at which the release of ATP per cell is maximal.
The cover was inspired by the systematic numerical study we conducted on varying hematocrit and vessel size. By combining the outcome of full simulation and the behavior of a dilute and concentrated suspension, the cover illustrates how real blood flow, involving several non-trivial factors (such as flow, RBC deformation, and many-body interactions), can be reduced to a simple drawing.
Through our systematic analysis and this cover, we illustrated the relevant key elements behind the emergence of a specific hematocrit leading to a maximal ATP release and highlighted the universality of this behavior, which should survive in complex vascular networks. This offers basic elements for future analyses aiming to understand ATP patterns and their relationship with cardiovascular diseases.
- Zhe Gou, Hengdi Zhang, Mehdi Abbasi, and Chaouqi Misbah