Red Blood Cell–Derived ATP as a Regulator of Skeletal Muscle Perfusion

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Abstract
Blood flow to skeletal muscle is a complex process designed to provide adequate, yet not excessive, amounts of oxygen to meet the ever-changing metabolic needs of the tissue. To accomplish this goal, a mechanism must exist that couples the oxygen needs of the tissue with the oxygen delivery system. A number of mechanisms have been investigated that have focused primarily on the vessel or tissue supplied. However, because none of these was able to adequately explain the precision inherent in oxygen supply, we began to investigate the potential role of the mobile oxygen carrier itself, the red blood cell. This review will provide evidence in support of the idea that the red blood cell is able to both sense oxygen need and evoke changes in blood flow to meet that need. In this scheme, as a red blood cell enters a region of increased metabolic demand relative to supply, the fall in hemoglobin oxygen saturation evokes the release of ATP, found within the red blood cell in mM amounts. The released ATP binds to purinergic receptors located on the vascular endothelium and induces a vasodilation that is conducted upstream increasing oxygen supply to the region of tissue supplied by the vessel. Although this mechanism is likely only one component of a complex system, which precisely regulates blood flow, we suggest that it plays a vital role in the regulation of perfusion distribution within tissue.