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Noradrenaline released from locus coeruleus axons contracts cerebral capillary pericytes via α 2 adrenergic receptors
Open accessAbstract
Noradrenaline (NA) release from locus coeruleus axons generates vascular contractile tone in arteriolar smooth muscle and contractile capillary pericytes. This tone allows neuronal activity to evoke vasodilation that increases local cerebral blood flow (CBF). Much of the vascular resistance within the brain is located in capillaries and locus coeruleus axons have NA release sites closer to pericytes than to arterioles. In acute brain slices, NA contracted pericytes but did not raise the pericyte cytoplasmic Ca 2+ concentration, while the α 1 agonist phenylephrine did not evoke contraction. Blocking α 2 adrenergic receptors (α 2 Rs, which induce contraction by inhibiting cAMP production), greatly reduced the NA-evoked pericyte contraction, whereas stimulating α 2 Rs using xylazine (a sedative) or clonidine (an anti-hypertensive drug) evoked pericyte contraction. Noradrenaline-evoked pericyte contraction and capillary constriction are thus mediated via α 2 Rs. Consequently, α 2 Rs may not only modulate CBF in health and pathological conditions, but also contribute to CBF changes evoked by α 2 R ligands administered in research, veterinary and clinical settings.
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Norepinephrine is a potent vasoconstrictor.
“NE is known to be a potent vasoconstrictor36,37.”
From Norepinephrine-mediated slow vasomotion drives glymphatic clearance during sleep (2025) · cites this paper as [37]
The Results report that noradrenaline constricted cerebral capillaries near pericytes, and the Discussion says it evokes contractile tone in cerebral arterioles and capillaries (page numbers unavailable). This supports its vasoconstrictor action, but the paper does not establish the broader claim that it is a potent vasoconstrictor generally. (LLM, conf=0.82)
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Glial and neuronal control of brain blood flow
Attwell, D., Buchan, A. M., Charpak, S., Lauritzen, M., MacVicar, B. A., & Newman, E. A. (2010) · Nature · doi:10.1038/nature09613 · Cited by 2,511
Self-citationA molecular atlas of cell types and zonation in the brain vasculature
Vanlandewijck, M., He, L., Mäe, M. A., Andrae, J., Ando, K., Del Gaudio, F., Nahar, K., Lebouvier, T., Laviña, B., Gouveia, L., et al. (2018) · Nature · doi:10.1038/nature25739 · Cited by 1,892
Capillary pericytes regulate cerebral blood flow in health and disease
Hall, C. N., Reynell, C., Gesslein, B., Hamilton, N. B., Mishra, A., Sutherland, B. A., O’Farrell, F. M., Buchan, A. M., Lauritzen, M., & Attwell, D. (2014) · Nature · doi:10.1038/nature13165 · Cited by 1,870
Self-citationAmyloid β oligomers constrict human capillaries in Alzheimer's disease via signaling to pericytes
Nortley, R., Korte, N., Izquierdo, P., Hirunpattarasilp, C., Mishra, A., Jaunmuktane, Z., Kyrargyri, V., Pfeiffer, T., Khennouf, L., Madry, C., et al. (2019) · Science · doi:10.1126/science.aav9518 · Cited by 682
Self-citationJohnson, E. C. B., Carter, E. K., Dammer, E. B., Duong, D. M., Gerasimov, E. S., Liu, Y., Liu, J., Betarbet, R., Ping, L., Yin, L., et al. (2022) · Nature Neuroscience · doi:10.1038/s41593-021-00999-y · Cited by 561
Marsh, S. E., Walker, A. J., Kamath, T., Dissing-Olesen, L., Hammond, T. R., de Soysa, T. Y., Young, A. M. H., Murphy, S., Abdulraouf, A., Nadaf, N., et al. (2022) · Nature Neuroscience · doi:10.1038/s41593-022-01022-8 · Cited by 431 · cited 1×
“30 The use of improved dissociation protocols for RNA sequencing, 31 spatial transcriptomic approaches (that use intact tissue sections) and development of specific antibodies against adrenergic receptors may be required to further assess the adrenergic receptor expression profile in pericytes.”
MethodMarsh, S. E., Kamath, T., Walker, A. J., Dissing-Olesen, L., Hammond, T. R., Young, A. M. H., Abdulraouf, A., Nadaf, N., Dufort, C., Murphy, S., et al. (2020) · doi:10.1101/2020.12.03.408542 · Cited by 430
Adrenergic receptors and cardiovascular effects of catecholamines
Motiejunaite, J., Amar, L., & Vidal-Petiot, E. (2021) · Annales d'Endocrinologie · doi:10.1016/j.ando.2020.03.012 · Cited by 296 · cited 2×
“11 Here we have investigated how NA affects the contractile tone of capillary pericytes, because capillaries comprise the majority of the resistance to cerebral blood flow within the brain parenchyma.”
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Cited by
Sorted by citations
Norepinephrine-mediated slow vasomotion drives glymphatic clearance during sleep
Hauglund, N. L., Andersen, M., Tokarska, K., Radovanovic, T., Kjaerby, C., Sørensen, F. L., Bojarowska, Z., Untiet, V., Ballestero, S. B., Kolmos, M. G., et al. (2025) · Cell · doi:10.1016/j.cell.2024.11.027 · Cited by 349
Plastic vasomotion entrainment
Sasaki, D., Imai, K., Ikoma, Y., & Matsui, K. (2024) · eLife · doi:10.7554/elife.93721.3 · Cited by 6
Metadata
- Authors
- Korte, N., James, G., You, H., Hirunpattarasilp, C., Christie, I., Sethi, H., & Attwell, D.
- Affiliations
- University College London (GB)
- Great Ormond Street Hospital (GB)
- Chulabhorn Royal Academy (TH)
- National Hospital for Neurology and Neurosurgery (GB)
- Corresponding author
- Attwell, David
- Venue
- Journal of Cerebral Blood Flow & Metabolism
- Publisher
- SAGE Publications
- Published
- 2023-01-23
- Volume
- 43
- Issue
- 7
- Pages
- 1142-1152
- ISSN
- 0271-678X (ISSN-L)
- 1559-7016
- PMC
- PMC10291462
- OpenAlex
- W4317780814
- Cited by
- 49
- References
- 8
- Citations by year
- 2026: 8 · 2025: 16 · 2024: 17 · 2023: 8
- FWCI
- 5.28
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Cerebral Blood Flow & Metabolism (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- UCL Discovery (University College London) (submittedVersion, cc-by-nc)
- Funders
- Wellcome Trust (099222/Z/12/Z, 099222)
- Medical Research Council (MR/T005297/1)
- Biotechnology and Biological Sciences Research Council
- H2020 European Research Council (740427)
- Topics
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Health Sciences › Medicine › Clinical Neurology › Traumatic Brain Injury and Neurovascular Disturbances
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- norepinephrine, locus coeruleus, capillary pericytes, alpha2-adrenoceptors, pericyte contraction, cerebral blood flow, cyclic AMP, xylazine, clonidine, phenylephrine
- MeSH terms
- Axons, Capillaries, Locus Coeruleus, Norepinephrine, Receptors, Adrenergic, alpha-2, Pericytes
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