Fig. 5

Model of microvascular autoregulation. a Pathways involved in microvascular autoregulation. At the model center (green square) is red blood cell (RBC) O₂-dependent ATP efflux, where RBCs act as signal transducers responding to local O₂ gradients, shear stress and metabolic conditions. Blue dots (A–A2) indicate normal microvascular function whereby partial pressure of oxygen (PO₂) gradients or RBC deformation [36–38] induce RBCs to release ATP, triggering a conducted vascular response leading to increased capillary RBC supply rate [10, 11, 16], matching local O₂ delivery with demand. Red dots indicate negative feedback on RBC O₂-dependent ATP efflux by nitric oxide (NO) [24], lactate [43] and decreased RBC deformability [42] (dashed red boxes). Multiple effects of NO on microvascular autoregulation, O₂ transport and O₂ consumption (orange dots (S1–S6)) include: S1, inhibiting RBC O₂-dependent ATP efflux [24]; S2, reducing conducted vascular response [9, 25]; S3, decreasing RBC deformability [22]; S4, inhibiting mitochondrial function [26] and O₂ consumption [2]; S5, inducing vasodilation, but altering vasoreactivity by inducing arteriolar hyporesponsiveness [28–30]. Sepsis increases lactate (S6) via tissue hypoxia or pyruvate dehydrogenase (PDH) phosphorylation [31], which decreases RBC O₂-dependent ATP efflux. Sepsis impaired microvascular autoregulation is manifested by increased capillary response time within hypoxic capillaries, attenuated RBC O₂-dependent ATP efflux, increased capillary stopped-flow [2, 4, 5] and low capillary venular end O₂ supply rates. b A flow chart of the model, where blue arrows trace normal microvascular autoregulation, red arrows show negative feedback on RBC O₂-dependent ATP efflux and orange arrows indicate NO-mediated effects. Dashed lines show relationships to microvascular function and autoregulation during sepsis. i/nNOS Inducible/neuronal nitric oxide synthase, qO₂ Capillary O₂ supply, VO₂ O₂ consumption