Endothelial alpha globin is a nitrite reductase

Resistance artery vasodilation in response to hypoxia is essential for matching tissue oxygen and demand. In hypoxia, erythrocytic hemoglobin tetramers produce nitric oxide through nitrite reduction. We hypothesized that the alpha subunit of hemoglobin expressed in endothelium also facilitates nitrite reduction proximal to smooth muscle. Here, we create two mouse strains to test this: an endothelial-specific alpha globin knockout (EC Hba1 Delta/Delta) and another with an alpha globin allele mutated to prevent alpha globin's inhibitory interaction with endothelial nitric oxide synthase (Hba1WT/Delta 36-39). The EC Hba1 Delta/Delta mice had significantly decreased exercise capacity and intracellular nitrite consumption in hypoxic conditions, an effect absent in Hba1WT/Delta 36-39 mice. Hypoxia-induced vasodilation is significantly decreased in arteries from EC Hba1 Delta/Delta, but not Hba1WT/Delta 36-39 mice. Hypoxia also does not lower blood pressure in EC Hba1 Delta/Delta mice. We conclude the presence of alpha globin in resistance artery endothelium acts as a nitrite reductase providing local nitric oxide in response to hypoxia. In mammals, hypoxia causes dilation of small arteries for increased metabolic demand. Keller et al used novel transgenic mice to show alpha hemoglobin in endothelium, once thought only in red blood cells, can regulate hypoxic-mediated dilation.

Automated summary

The presence of alpha globin in endothelium of resistance arteries facilitates nitrite reduction and nitric oxide production in response to hypoxia, influencing vasodilation and exercise capacity.