Erythrocytes: oxygen sensors and modulators of vascular tone

Abstract

Through oxygen-dependent release of the vasodilator ATP, the mobile erythrocyte plays a fundamental role in matching microvascular oxygen supply with local tissue oxygen demand. Signal transduction within the erythrocyte and microvessels as well as feedback mechanisms controlling ATP release have been described. Our understanding of the impact of this novel control mechanism will rely on the integration of in vivo experiments and computational models.

Figure 1

A. Oxygen supply to tissue is generally conceptualized based on the simple Krogh tissue cylinder model in which all oxygen exchange occurs across the walls of the capillaries. As such, oxygen content within the capillary falls linearly as oxygen diffuses out of the vessel at a constant rate. B. Our current understanding of the complex oxygen transport pathways controlling oxygen supply include convective oxygen transport through the microvessels (solid line) coupled with diffusive oxygen exchange (dotted lines) among all orders of microvessels. The appropriate delivery of oxygen to the tissue requires a mechanism to sense oxygen need and alter blood flow to meet that need which can be flexible enough to compensate for alterations in both convective and diffusive transport.

Figure 2

Impact of diffusional oxygen losses on the distribution of oxygen into downstream vessels. The lower hematocrit (a consequence of the cell free plasma layer) and oxygen saturation (due to diffusional oxygen losses) near the arteriolar wall results in the distribution of red blood cells and oxygen into the side branch which is not proportional to the blood flow (panel B). Vasoconstriction of the side branch (panel A) reduces both hematocrit and O₂ saturation in that vessel while vasodilation (panel C) increases both hematocrit and O₂ saturation. Higher O₂ saturation along vessel centerline designated by bright red erythrocytes; lower saturation near wall by cells with increasing levels of purple

Figure 3

The entrance of erythrocytes into tissue regions with a high oxygen demand [decreased oxygen tension (PO₂)] results in diffusion of oxygen to the tissue and a decrease in the oxygen saturation (SO₂) of the hemoglobin within erythrocytes in the microcirculation. This decrease in SO₂ stimulates the release of ATP from the erythrocyte via activation of a signaling pathway (see text) with the amount released proportional to the decrease in SO₂. The erythrocyte-derived ATP can then interact with endothelial purinergic receptors resulting in the production of mediators that initiate vasodilation. This vasodilation is conducted in a retrograde fashion resulting in increased blood flow (oxygen supply) to areas of increased oxygen demand. Abbreviations: Gi = heterotrimeric G protein; ATP = adenosine triphosphate; cAMP = 3’5’-adenosine monophosphate; PKA = protein kinase A; CFTR = cystic fibrosis transmembrane conductance regulator; ? = an as yet unidentified conduit for ATP release; PR = purinergic receptors; + = stimulation, endo = endothelium; SMC = smooth muscle cell.

Figure 4

Proposed activation of endothelium-dependent and -independent vasodilation which occurs following the release of ATP from erythrocytes. Activation of erythrocyte Gi results in increased adenylyl cyclase (4,28) resulting in increased cAMP followed downstream by increased ATP release. Paracrine activation of endothelial P_2y receptors (46,47,97) by erythrocyte-derived ATP release couples with G_q/11 to stimulate PLC that increases InsP₃ synthesis. InsP₃ activates its receptor on the ER promoting the release of ER stored Ca⁺⁺ (8). Depletion of Ca⁺⁺ from the ER stimulates Ca⁺⁺ entry through membrane SOC channels. Increased intracellular Ca⁺⁺ activates eNOS to synthesize NO, cPLA₂ to release AA from membrane phospholipids for synthesis of PGI₂ and EDHF (7,32,62). Endothelium-released NO activates sGC in the underlying smooth muscle to increase cGMP synthesis (32) and inhibits erythrocyte Gi to reduce ATP release (67,69). PGI₂ acts on its smooth muscle G_s-coupled IP receptor to stimulate adenylyl cyclase to increase cAMP synthesis. Both increased cGMP and cAMP promote vascular smooth muscle cell relaxation, and dilation. EDHF acts on a K_Ca++ channel on the vascular smooth muscle plasma membrane to increase K⁺ efflux, hyperpolarizing the smooth muscle cell that results in its relaxation. ATP released from the erythrocyte can act in an autocrine manner by activating erythrocyte P2x₇ receptors (34) that increase Ca⁺⁺ uptake activating PLA₂ activity and EET synthesis and release (52). The EETs act directly on a vascular K_Ca++ channel to hyperpolarize and relax the smooth muscle cell (8,31). Also in an autocrine manner, ADP, derived from released ATP can activate the erythrocyte P2y₁₃ receptor that results in a decrease in erythrocyte cAMP and decreases erythrocyte ATP release (95). Endothelial and/or smooth muscle cell hyperpolarization resulting from K⁺ efflux can conduct through gap junctions to adjacent cells resulting in conducted vasodilation. (76-78) AA, arachidonic acid; ACII, adenylyl cyclase II; ADP adenosine diphosphate; ATP, adenosine triphosphate; cAMP, 3’,5’- cyclic adenosine monophosphate; cGMP, 3’,5’- cyclic guanosine monophosphate; EDHF, endothelium-derived hyperpolarizing factor; EETs, epoxyeicosatrienoic acids; eNOS, endothelial nitric oxide synthase; ER, endoplasmic reticulum; G_i, G_q, and G_s: guanine nucleotide protein I, q and s-coupled receptors, respectively; IP, prostacyclin receptor; K_Ca++, calcium-activated potassium channel; K_IR, inward rectifying potassium channel; NO, nitric oxide; P2x, ligand gated ion channel purinergic receptor; P2y, G protein-coupled purinergic receptor; PGI₂, prostacyclin; cPLA₂, cytosolic phospholipase A₂; PLC, phospholipase C; sGC, soluble guanylyl cyclase; SOC, store-operated calcium channel, GAP, gap junction.