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Optimal hematocrit for proper blood flow regulation by ATP

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Biochemical signaling by red blood cells (RBCs) is essential for proper regulation of blood flow, and understanding it allows the design of
therapies adapted to cardiovascular pathologies. The release of ATP (Adenosine Triphosphate) by RBCs is a major mechanism that has been modeled in this work, revealing the existence of an optimal hematocrit for better ATP release.

The vascular network is a complex biochemical signaling site, in which different types of cells participate, such as red blood cells, white blood cells, and endothelial cells (which line the inner surfaces of blood vessels). An alteration of this signaling is at the origin of multiple dysfunctions leading to cardiovascular pathologies, the first cause of mortality in the world. How ATP release from red blood cells optimizes blood flow regulation in vascular networks requires complex modeling and simulation involving blood flow, its interaction with the endothelium, and the reactions and transport of biochemical elements involved. Researchers from the Interdisciplinary Laboratory of Physics (LIPhy, CNRS/University of Grenoble Alpes, have taken up this challenge and demonstrated the existence of an optimal operating point.

Although red blood cells are often described as oxygen cargo ships, their true function goes far beyond this simplistic image. In reality, they also transport numerous macromolecules, the most emblematic of which is ATP. ATP is released by RBCs in case of hypoxia, for example. The released ATP reacts with the inner vascular wall (lined with so-called endothelial cells) inducing a release of calcium (stored in the endothelial cells) which then produces NO (Nitrate Oxide), a vasodilator. By this mechanism blood flow is increased to compensate for the drop in oxygen. A reduction of ATP release by RBCs is associated with pathologies such as, among others, type II diabetes and cystic fibrosis (a genetic disease that mainly affects the lungs and the digestive system). A priori, one might think that increasing hematocrit would be accompanied by an increase in the concentration of ATP released into the blood plasma. This naive reasoning is challenged : an optimum of ATP release requires a particular hematocrit, above or below which the release of ATP by RBCs falls (Fig. 1a). This conclusion was made possible by a detailed study of the different mechanisms involved, such as the interactions of RBCs with each other and with the vascular walls, their permanent deformations, and the conformational changes of protein channels regulating ATP release.

In this work, the researchers proposed a model of ATP release by taking into account, in addition to the interactions between blood cells and with the vascular walls, the conformational changes of a membrane protein allowing the local release of ATP by a mechanotransduction mechanism due to the hydrodynamic constraints that prevail in the blood vessels. When the hematocrit is low, each cell acts as if it were alone and the effects of ATP release are additive : the more cells, the better. However, and this is the main point of the present discovery : above a critical hematocrit, the cells no longer act as if they were alone, some are in the periphery (and thus subjected to a higher hydrodynamic stress, and thus release more ATP), on the other hand others are pushed back to the center of the vessel where the stress is low (Fig.1b), thus inhibiting ATP release. In addition, each cell is shielded by the others, making the effect of the stresses less effective overall. It is the subtle nonlinear competition between these three effects that results in an optimal hematocrit for better ATP release (Fig. 1a).

This work opens many perspectives for systematic simulation involving blood flow and biochemical signaling in real vascular networks from medical imaging. It should help to understand how, for example, the formation of blood aggregates, persisting in the vascular networks of patients with diabetes, can alter the release of ATP, and thus better guide research for the development of appropriate therapies.

Figure 1 : Left : ATP levels as a function of hematocrit. Right : the configuration of red blood cells with σmem the hydrodynamic stress of the RBC membrane showing that RBCs at the periphery have a higher value than those in the center.

On the cover of Biophysical Journal issue of November


Voir en ligne : Red blood cells under flow show maximal ATP release for specific hematocrit, Zhe Gou Hengdi Zhang Mehdi Abbasi Chaouqi Misbah