Author:
Keller T.C. Stevenson,Keller Alexander S.,Brás Broseghini-Filho Gilson,Butcher Joshua T.,Page Henry R. Askew,Islam Aditi,Tan Zhe Yin,DeLalio Leon J.,Lechauve Christophe,Brooks Steven,Sharma Poonam,Hong Kwangseok,Xu Wenhao,Simão Padilha Alessandra,Ruddiman Claire A.,Best Angela K.,Macal Edgar,Kim-Shapiro Daniel B.,Christ George,Yan Zhen,Cortese-Krott Miriam M.,Ricart Karina,Patel Rakesh,Bender Timothy P.,Sonkusare Swapnil K.,Weiss Mitchell J.,Ackerman Hans,Columbus Linda,Isakson Brant E.
Abstract
AbstractSmall 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.
Publisher
Cold Spring Harbor Laboratory
Cited by
2 articles.
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