Erythrocyte‐derived ATP and Perfusion Distribution: Role of Intracellular and Intercellular Communication

Abstract

In complex organisms, both intracellular and intercellular communication is critical for the appropriate regulation of the distribution of perfusion to assure optimal oxygen (O2) delivery and organ function. The mobile erythrocyte is in a unique position in the circulation since it both senses and responds to a reduction in O2 tension in its environment. When erythrocytes enter a region of the microcirculation in which O2 tension is reduced, they release both O2 and the vasodilator, adenosine triphosphate (ATP) via activation of a specific and dedicated signaling pathway that requires increases in cAMP, that are regulated by phosphodiesterase 3B. The ATP released initiates a conducted vasodilation that results in alterations in the distribution of perfusion to meet the tissue’s metabolic needs. This delivery mechanism is modulated by both positive and negative feedback regulators. Importantly, defects in low O2-induced ATP release from erythrocytes have been observed in several human disease states in which impaired vascular function is present. Understanding of the role of erythrocytes in controlling perfusion distribution and the signaling pathways that are responsible for ATP release from these cells makes the erythrocyte a novel therapeutic target for the development of new approaches for the treatment of vascular dysfunction.

Nitric Oxide–Dependent Feedback Loop Regulates Transient Receptor Potential Vanilloid 4 (TRPV4) Channel Cooperativity and Endothelial Function in Small Pulmonary Arteries

“…Purinergic signaling is an essential component to the pulmonary vasculature,59, 60, 61, 62, 63 and ATP activation of TRPV4 channels represents a mechanism that may link physiological stimuli to the regulation of pulmonary vascular function. ATP can be released from sympathetic nerves during synaptic transmission, or can be released into the circulation by ECs, SMCs, or erythrocytes 25, 26, 64, 65. Shear stress, which is a well‐known activator of endothelial TRPV4 channels,66, 67, 68 also induces the release of ATP,65 suggesting a possible involvement of P2 purinergic receptor‐TRPV4 signaling in flow‐induced vasodilation.…”

“…In this regard, purinergic receptor agonist ATP has been shown to increase endothelial Ca 2+ and cause vasodilation in large, conduit PAs 22, 23, 24. ATP can be released into the circulation by ECs, smooth muscle cells (SMCs), and red blood cells 25, 26. Circulatory ATP may, therefore, serve as an important regulator of pulmonary vascular resistance.…”

The purinergic neurotransmitter revisited: A single substance or multiple players?

“…It is important to note that release of ATP has been shown in all major cell types of the vessel wall including vascular endothelium (Sedaa et al, 1990; Hassessian et al, 1993; Shinozuka et al, 1994) and smooth muscle (Vizi & Burnstock, 1988; Sedaa et al, 1990; Vizi et al, 1992), as well as circulating erythrocytes and platelets (Sprague et al, 1996; Sprague & Ellsworth, 2012) (see also Lohman et al, 2012). The endothelium appears to be the major source of purines in the vasculature.…”

The Physiologic Role of Erythrocytes in Oxygen Delivery and Implications for Blood Storage

“…8,9 The released ATP elicits a vasodilator response locally and in the surrounding microcirculation that occurs in about 0.5 second. 10 It seems that the low-oxygen induced ATP release is triggered by the desaturation of RBC-membrane bound Hb molecules; that is, structural change in these deoxygenated Hb molecules elicits a structural deformation in the RBC membrane and subsequent ATP release.…”