Endothelial cell expression of haemoglobin α regulates nitric oxide signalling

Nature. 2012 Nov 15;491(7424):473-7. doi: 10.1038/nature11626. Epub 2012 Oct 31.


Models of unregulated nitric oxide (NO) diffusion do not consistently account for the biochemistry of NO synthase (NOS)-dependent signalling in many cell systems. For example, endothelial NOS controls blood pressure, blood flow and oxygen delivery through its effect on vascular smooth muscle tone, but the regulation of these processes is not adequately explained by simple NO diffusion from endothelium to smooth muscle. Here we report a new model for the regulation of NO signalling by demonstrating that haemoglobin (Hb) α (encoded by the HBA1 and HBA2 genes in humans) is expressed in human and mouse arterial endothelial cells and enriched at the myoendothelial junction, where it regulates the effects of NO on vascular reactivity. Notably, this function is unique to Hb α and is abrogated by its genetic depletion. Mechanistically, endothelial Hb α haem iron in the Fe(3+) state permits NO signalling, and this signalling is shut off when Hb α is reduced to the Fe(2+) state by endothelial cytochrome b5 reductase 3 (CYB5R3, also known as diaphorase 1). Genetic and pharmacological inhibition of CYB5R3 increases NO bioactivity in small arteries. These data reveal a new mechanism by which the regulation of the intracellular Hb α oxidation state controls NOS signalling in non-erythroid cells. This model may be relevant to haem-containing globins in a broad range of NOS-containing somatic cells.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenergic alpha-1 Receptor Agonists / pharmacology
  • Animals
  • Cells, Cultured
  • Diffusion
  • Endothelial Cells / drug effects
  • Endothelial Cells / enzymology
  • Endothelial Cells / metabolism*
  • Gene Expression Profiling
  • Gene Expression Regulation* / drug effects
  • Hemoglobins / genetics
  • Hemoglobins / metabolism*
  • Humans
  • Iron / chemistry
  • Mice
  • Nitric Oxide / metabolism*
  • Nitric Oxide Synthase / metabolism
  • Oxidation-Reduction
  • Peptide Fragments / genetics
  • Peptide Fragments / metabolism*
  • Phenylephrine / pharmacology
  • Signal Transduction*


  • Adrenergic alpha-1 Receptor Agonists
  • Hemoglobins
  • Peptide Fragments
  • alpha(A) globin
  • Phenylephrine
  • Nitric Oxide
  • Iron
  • Nitric Oxide Synthase