Endothelial cell expression of haemoglobin α regulates nitric oxide signalling
Open accessAbstract
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.
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Hb-α is expressed in myoendothelial junctions in resistance vessels without its β subunit partner.
“Hb-α was found to be expressed in myoendothelial junctions (connection between endothelium and smooth muscle) in resistance vessels without its β subunit partner (172).”
From Red Blood Cell Function and Dysfunction: Redox Regulation, Nitric Oxide Metabolism, Anemia (2017) · cites this paper as [172]
Fine-tuning of NO diffusion from the endothelium to the smooth muscle cell is controlled by regulation of its Fe2+/Fe3+ redox equilibrium.
“Fine-tuning of NO diffusion from the endothelium to the smooth muscle cell is controlled by regulation of its Fe2+/Fe3+ redox equilibrium (172).”
From Red Blood Cell Function and Dysfunction: Redox Regulation, Nitric Oxide Metabolism, Anemia (2017) · cites this paper as [172]
The magnitude of NO signaling is a function of the redox state of Hbα expressed in human arterial endothelial cells.
“An elegant study has demonstrated that the magnitude of NO signaling is a function of the redox state of a specific hemoglobin, Hbα, which is expressed in human arterial endothelial cells [81].”
From Signaling and stress: The redox landscape in NOS2 biology (2015) · cites this paper as [81]
The findings underline the sensitivity and power of single-cell transcriptomics to reveal differences in cell identities and changes within individual cell types under different treatments and conditions, including organismal aging.
“Our findings, in agreement with recent studies, underline the sensitivity and power of single-cell transcriptomics not only to reveal differences in cell identities, but also to reveal changes within individual cell types under different treatments and conditions 23,26,27,70 , including organismal aging 59,60 .”
From Single-cell transcriptomic profiling of the aging mouse brain (2019) · cites this paper as [70]
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Self-citation
- Authors
- Straub, A. C., Lohman, A. W., Billaud, M., Johnstone, S. R., Dwyer, S. T., Lee, M. Y., Bortz, P. S., Best, A. K., Columbus, L., Gaston, B., & Isakson, B. E.
- Affiliations
- University of Virginia (US)
- Corresponding author
- Isakson, Brant E.
- ORCID
- Venue
- Nature
- Published
- 2012-10-31
- Volume
- 491
- Issue
- 7424
- Pages
- 473-477
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC3531883
- OpenAlex
- W2154811651
- Cited by
- 308
- References
- 31
- Citations by year
- 2026: 17 · 2025: 22 · 2024: 21 · 2023: 25 · 2022: 28 · 2021: 33 · 2020: 21 · 2019: 17 · 2018: 21 · 2017: 31 · 2016: 18 · 2015: 17 · 2014: 19 · 2013: 16 · 2012: 2
- FWCI
- 11.49
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- ENLIGHTEN (Jurnal Bimbingan dan Konseling Islam) (submittedVersion)
- Funders
- Yale University
- University of Virginia
- National Heart, Lung, and Blood Institute (P01HL101871, HL101871, R01HL059337, R21HL107963, HL059337, R56HL059337, HL-107963, R00HL112904, K99HL112904, U10HL109250, R01HL088554, HL-088554, HL-112904, HL007284, T32HL007284)
- Topics
- Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Hemoglobin structure and function
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heme Oxygenase-1 and Carbon Monoxide
- Keywords
- nitric oxide signaling, CYB5R3, myoendothelial gap junctions, S-nitrosothiols, nitric oxide diffusion, vascular smooth muscle, endothelial nitric oxide synthase, haem iron, vascular tone, alpha-adrenergic agonists, endothelium-dependent relaxation
- MeSH terms
- Animals, Cells, Cultured, Diffusion, Gene Expression Regulation, Hemoglobins, Humans, Iron, Nitric Oxide, Oxidation-Reduction, Peptide Fragments, Phenylephrine, Signal Transduction, Nitric Oxide Synthase, Gene Expression Profiling, Endothelial Cells, Mice, Adrenergic alpha-1 Receptor Agonists
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