Capillary pericytes regulate cerebral blood flow in health and disease
Open accessAbstract
Increases in brain blood flow, evoked by neuronal activity, power neural computation and form the basis of BOLD (blood-oxygen-level-dependent) functional imaging. Whether blood flow is controlled solely by arteriole smooth muscle, or also by capillary pericytes, is controversial. We demonstrate that neuronal activity and the neurotransmitter glutamate evoke the release of messengers that dilate capillaries by actively relaxing pericytes. Dilation is mediated by prostaglandin E2, but requires nitric oxide release to suppress vasoconstricting 20-HETE synthesis. In vivo, when sensory input increases blood flow, capillaries dilate before arterioles and are estimated to produce 84% of the blood flow increase. In pathology, ischaemia evokes capillary constriction by pericytes. We show that this is followed by pericyte death in rigor, which may irreversibly constrict capillaries and damage the blood-brain barrier. Thus, pericytes are major regulators of cerebral blood flow and initiators of functional imaging signals. Prevention of pericyte constriction and death may reduce the long-lasting blood flow decrease that damages neurons after stroke.
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Pericytes play an active role in regulating cerebral blood flow.
“These findings coupled by recent physiological experiments on pericyte contractility support that pericytes play an active role in regulating CBF (65, 173, 228, 318, 319, 470).”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [228]
Binding of RAP-RL to RAGE may competitively inhibit RAGE-mediated Aβ transport into the brain.
“First, the binding of RAP‐RL to RAGE may competitively inhibit RAGE‐mediated Aβ transport into the brain, similar with the RAGE inhibiter Azeliragon.[ 40 ]”
From Multifunctional Nanostructure RAP‐RL Rescues Alzheimer's Cognitive Deficits through Remodeling the Neurovascular Unit (2021) · cites this paper as [40]
The sections on pericyte dilation and ischaemia discuss cerebral blood flow, capillary constriction, and pericyte death. Searches for RAP-RL, RAGE, Aβ transport, and Azeliragon found no passage in our copy addressing the proposed competitive inhibition of Aβ transport into the brain. (LLM, conf=0.76)
Experimental — accuracy not yet measuredThe mean distance between human pericytes was 65.3±0.4 μm (94 pericytes from 2 patients), 30% larger than in rodents.
“The mean distance between human pericytes was 65.3±0.4 μm (for 94 pericytes imaged in tissue from 2 patients), 30% larger than in rodents (19).”
From Amyloid β oligomers constrict human capillaries in Alzheimer's disease via signaling to pericytes (2019) · cites this paper as [19]
Contractile pericytes can alter cerebral blood flow by adjusting their contractile tone.
“can alter cerebral blood flow by adjusting their contractile tone (18–20).”
From Amyloid β oligomers constrict human capillaries in Alzheimer's disease via signaling to pericytes (2019) · cites this paper as [19]
AD mice have APP with a humanised Aβ region containing 3 AD-related mutations (APPNL-G-F) knocked in, to avoid artefacts associated with over-expressing APP.
“AD mice, in which APP with a humanised Aβ region containing 3 AD-related mutations (APPNL-G-F) is knocked in (49), to avoid artefacts associated with over-expressing APP, were crossed with NG2-DsRed mice in which pericytes express DsRed (19).”
From Amyloid β oligomers constrict human capillaries in Alzheimer's disease via signaling to pericytes (2019) · cites this paper as [19]
The data in Fig. 4 were averaged over all visible pericytes in the images, and so already take account of the fact that the contractility of capillary pericytes decreases for higher branching orders of capillary.
“Importantly, the data in Fig. 4 were averaged over all visible pericytes in the images, and so already take account of the fact that the contractility of capillary pericytes decreases for higher branching orders of capillary (19).”
From Amyloid β oligomers constrict human capillaries in Alzheimer's disease via signaling to pericytes (2019) · cites this paper as [19]
The contractility of capillary pericytes decreases for higher branching orders of capillary.
“the contractility of capillary pericytes decreases for higher branching orders of capillary (19)”
From Amyloid β oligomers constrict human capillaries in Alzheimer's disease via signaling to pericytes (2019) · cites this paper as [19]
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“Throughout the release of messengers including prostaglandin E2, neuronal activity and the neurotransmitter glutamate can dilate capillaries by relaxing pericytes (Hall et al., 2014).”
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- Authors
- 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.
- Affiliations
- University College London (GB)
- University of Copenhagen (DK)
- University of Oxford (GB)
- Corresponding author
- Lauritzen, Martin
- Attwell, David
- ORCID
- Venue
- Nature
- Published
- 2014-03-26
- Volume
- 508
- Issue
- 7494
- Pages
- 55-60
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC3976267
- OpenAlex
- W2001552996
- Cited by
- 1,870
- References
- 52
- Citations by year
- 2026: 135 · 2025: 140 · 2024: 169 · 2023: 152 · 2022: 173 · 2021: 211 · 2020: 189 · 2019: 132 · 2018: 150 · 2017: 141 · 2016: 123 · 2015: 113 · 2014: 39
- FWCI
- 72.02
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (publishedVersion)
- PubMed Central (acceptedVersion)
- eCite Digital Repository (University of Tasmania) (submittedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Figshare (submittedVersion, cc-by)
- Research Portal (King's College London) (submittedVersion)
- Funders
- Wellcome Trust (099222/Z/12/Z, 075232, 99222)
- Topics
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Health Sciences › Medicine › Neurology › Traumatic Brain Injury and Neurovascular Disturbances
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Advanced MRI Techniques and Applications
- Keywords
- capillary pericytes, cerebral blood flow, neuronal activity, glutamate, prostaglandin E2, nitric oxide, 20-hydroxyeicosatetraenoic acid, capillary dilation, cerebral ischemia, blood-brain barrier, stroke
- MeSH terms
- Animals, Arterioles, Blood-Brain Barrier, Capillaries, Cerebellum, Cerebral Cortex, Brain Ischemia, Cerebrovascular Circulation, Female, Hydroxyeicosatetraenoic Acids, Male, Mice, Inbred C57BL, Nitric Oxide, Vasoconstriction, Vasodilation, Dinoprostone, Signal Transduction, Cell Death, Rats, Sprague-Dawley, Rats, Wistar, Receptors, Glutamate, Excitatory Amino Acid Antagonists, Glutamic Acid, Pericytes, Stroke, Mice, Rats, Functional Neuroimaging, In Vitro Techniques
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