The coupling of hemoglobin sensing of physiological oxygen gradients to stimulation of nitric oxide (NO) bioactivity is an established principle of hypoxic blood flow. One mechanism proposed to explain this oxygen-sensing–NO bioactivity linkage postulates an essential role for the conserved Cys93 residue of the hemoglobin -chain (Cys93) and, specifically, for S-nitrosation of Cys93 to form S-nitrosohemoglobin (SNO-Hb)¹. The SNO-Hb hypothesis, which conceptually links hemoglobin and NO biology, has been debated intensely in recent years^{2, 3}. This debate has precluded a consensus on physiological mechanisms and on assessment of the potential role of SNO-Hb in pathology. Here we describe new mouse models that exclusively express either human wild-type hemoglobin or human hemoglobin in which the Cys93 residue is replaced with alanine to assess the role of SNO-Hb in red blood cell–mediated hypoxic vasodilation. Substitution of this residue, precluding hemoglobin S-nitrosation, did not change total red blood cell S-nitrosothiol abundance but did shift S-nitrosothiol distribution to lower molecular weight species, consistent with the loss of SNO-Hb. Loss of Cys93 resulted in no deficits in systemic or pulmonary hemodynamics under basal conditions and, notably, did not affect isolated red blood cell–dependent hypoxic vasodilation. These results demonstrate that SNO-Hb is not essential for the physiologic coupling of erythrocyte deoxygenation with increased NO bioactivity in vivo.

1. Department of Pathology and Center for Free Radical Biology, 901 19th Street South, Birmingham, Alabama 35294, USA.
2. Department of Biochemistry and Molecular Genetics, 502 20th Street South, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA.
3. Department of Pathology, 1501 Kings Highway, Louisiana State University Health Sciences Center, Shreveport, Louisiana 71130, USA.
4. Department of Cell Biology,1900 University Boulevard, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA.
5. Department of Pediatrics, 1670 University Boulevard, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA.
6. Department of Physiology and Biophysics 1918 University Boulevard, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA.
7. These authors contributed equally to this work.

Correspondence to: Rakesh P Patel¹ e-mail: rakeshp@uab.edu

Correspondence to: Tim M Townes² e-mail: ttownes@uab.edu

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