Beyond oxygen transport: active role of erythrocytes in the regulation of blood flow

It was classically thought that the function of mammalian red blood cells (RBCs) was limited to serving as a vehicle for oxygen, given the cells' abundance of cytosolic hemoglobin. Over the past decades, however, accumulating evidence indicates that RBCs have the capacity to sense low-oxygen tensions in hypoxic tissues, and, subsequently, release signaling molecules that influence the distribution of blood flow. The precise mechanisms that facilitate RBC modulation of blood flow are still being elucidated, although recent evidence indicates involvement of 1) adenosine triphosphate, capable of binding to purinergic receptors located on the vascular wall before initiating nitric oxide (NO; a powerful vasodilator) production in endothelial cells, and/or 2) nonvascular NO, which is now known to have several modes of production within RBCs, including an enzymatic process via a unique isoform of NO synthase (i.e., RBC-NOS), which has potential effects on the vascular smooth muscle. The physical properties of RBCs, including their tendency to form three-dimensional structures in low shear flow (i.e., aggregation) and their capacity to elongate in high shear flow (i.e., deformability), are only recently being viewed as mechanotransductive processes, with profound effects on vascular reactivity and tissue perfusion. Recent developments in intracellular signaling in RBCs, and the subsequent effects on the mechanical properties of blood, and blood flow, thus present a vivid expansion on the classic perspective of these abundant cells.