Hemoglobin, nitric oxide and molecular mechanisms of hypoxic vasodilation

Abstract

The protected transport of nitric oxide (NO) by hemoglobin (Hb) links the metabolic activity of working tissue to the regulation of its local blood supply through hypoxic vasodilation. This physiologic mechanism is allosterically coupled to the O(2) saturation of Hb and involves the covalent binding of NO to a cysteine residue in the beta-chain of Hb (Cys beta93) to form S-nitrosohemoglobin (SNO-Hb). Subsequent S-transnitrosation, the transfer of NO groups to thiols on the RBC membrane and then in the plasma, preserves NO vasodilator activity for delivery to the vascular endothelium. This SNO-Hb paradigm provides insight into the respiratory cycle and a new therapeutic focus for diseases involving abnormal microcirculatory perfusion. In addition, the formation of S-nitrosothiols in other proteins may regulate an array of physiological functions.

Figure 1

Hypoxic vasodilation. (a) RBCs containing oxygenated Hb (R-state) approaching a microvascular branch point (i) are preferentially directed to a dilated capillary that supplies actively metabolizing tissue because desaturation of preceding RBCs (ii) has caused the allosteric release of NO bioactivity in the form of SNOs. RBCs containing deoxygenated Hb (T-state) enter the venous system where NO from several sources in the plasma as well as from SNO-Hb (thiol to heme transfer) recharge the HbFe- NO stores (iii) by binding hemes in the β-chains, forming metHb-containing hybrids (Fe^III/NO). Re-oxygenation in the lungs (inset, iv) displaces NO from the hemes to β93 cysteines, restoring the dilator capacity of the RBCs. AE1, Anion Exchanger 1. (b) The contribution of RBC-transported NO bioactivity is shown in the graph, in which the straight descending line reflects the availability of O₂ without vasodilation. The shaded area represents the increased O₂ extraction enabled by hypoxic vasodilation (data from [15,20,22,85]).