Fig. 7

Model of three-levels of microvascular autoregulation. a–c Schematics of three levels of microvascular autoregulation: 1) the overall skeletal muscle capillary network, 2) the capillary and 3) the erythrocyte, respectively. a Microvascular autoregulation at the capillary network level is viewed as the integrated conducted vascular response over the entire network feeding back to the resistance vessels [45], where nitric oxide (NO) relaxes smooth muscle vasodilating feeding arterioles, causing downstream increases in capillary red blood cell (RBC) supply rate (SR) [10, 11]. The dashed green line represents the conducted vascular response. b At the capillary level is the interaction between vascular ATP (released by hypoxic RBCs) and purinergic type 2 (P2Y) receptors on endothelial cells, which trigger the conducted vascular response. c At the level of the hypoxic erythrocyte is the interaction (metabolic switch) between deoxyhemoglobin and cdb3 at the inner RBC membrane, where deoxyhemoglobin displaces glycolytic enzymes, triggering glycolysis and ATP release [13–15, 57, 58]. (Note, RBC O₂-dependent ATP release is inhibited by glycolytic inhibitors, CO [13] and NO [24]). The dashed circle in c shows two additional RBC mechanisms. While NO₂^– has been reported to function in hypoxic vasodilation whereby deoxyhemoglobin converts NO₂^– to NO [46, 56], its role in sepsis is unclear. Similarly, it is unclear how hemoglobin-derived S-nitrosothiol [59] would function as a vasodilator in the capillary network, as capillaries are not surrounded by smooth muscle. Art-end Arteriolar end of capillaries, cdb3 Cytoplasmic domain of band 3, eNOS endothelial nitric oxide synthase, GE Glycolytic enzymes, Hb Hemoglobin, LDH Lactate dehydrogenase, NO₂^– Nitrite, PFK Phosphofructokinase, qO₂ Capillary oxygen supply rate, R Relaxed Hb state, Smc Smooth muscle cell, SO₂ Oxygen saturation, T Tense Hb state, Ven-end Venular end of capillaries