Endothelial alpha globin is a nitrite reductase

Abstract

Small artery vasodilation in response to hypoxia is essential for matching oxygen supply to tissue oxygen demand. One source of hypoxic dilation via nitric oxide (NO) signaling is nitrite reduction by erythrocytic hemoglobin (α2β2). However, the alpha subunit of hemoglobin is also expressed in resistance artery endothelium and localized to myoendothelial junctions, a subcellular domain that contacts underlying vascular smooth muscle cells. We hypothesized that nitrite reduction mediated by endothelial alpha globin may occur at myoendothelial junctions to regulate hypoxic vasodilation. To test this concept, we created two novel mouse strains: one lacking alpha globin specifically in endothelium (EC Hba1Δ/Δ) and one where alpha globin is mutated such that its inhibitory association with endothelial NO synthase (eNOS) is prevented (Hba1WT/Δ36-39). In EC Hba1Δ/Δ or Hba1WT/Δ36-39 mice hemoglobin levels, hematocrit and erythrocyte counts were unchanged from littermate controls. Loss of the full alpha globin protein from the endothelium in the EC Hba1Δ/Δ model was associated with decreased exercise capacity and decreased intracellular nitrite utilization in hypoxic conditions. These effects were not seen in Hba1WT/Δ36-39 animals. Hypoxia induced vasodilation was decreased by 60% in isolated thoracodorsal arteries from EC Hba1Δ/Δ, while infusion of erythrocytes only partially rescued the dilatory response. Lastly, unlike other models where blood pressure is decreased, EC Hba1Δ/Δ blood pressure was not altered in response to hypoxia. Overall, we conclude that alpha globin in the resistance artery endothelium can act as a nitrite reductase to provide a local vasodilatory response to hypoxia.

Alpha globin gene copy number and hypertension risk among Black Americans

“…A vasodilatory role for alpha globin could be explained by its ability to function not only as a nitric oxide scavenger, but also as a nitric oxide producer via the reduction of nitrite under hypoxic conditions. 27 While the contribution of eNOS activity to vasodilation diminishes with age, the nitrite reductase activity of endothelial alpha globin could potentially persist, thereby explaining the unexpected association of higher HBA copy number with lower diastolic blood pressure in this study of older Black Americans.…”

“…This observation implies that increased expression of alpha globin is associated with lower blood pressure, rather than higher blood pressure as hypothesized. Keller et al recently demonstrated that endothelial alpha globin can produce nitric oxide from the chemical reduction of nitrite under hypoxic conditions [30]. Thus, endothelial alpha globin may function not only as a nitric oxide scavenger, but also as a nitric oxide producer.…”

Alpha globin gene copy number and hypertension risk among Black Americans

“…This observation implies that increased expression of alpha globin is associated with lower blood pressure, rather than higher blood pressure as hypothesized. Keller et al recently demonstrated that endothelial alpha globin can produce nitric oxide from the chemical reduction of nitrite under hypoxic conditions [ 29 ]. Thus, endothelial alpha globin may function not only as a nitric oxide scavenger, but also as a nitric oxide producer.…”