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Brain endothelial cell TRPA1 channels initiate neurovascular coupling

  1. Pratish Thakore
  2. Michael G Alvarado
  3. Sher Ali
  4. Amreen Mughal
  5. Paulo W Pires
  6. Evan Yamasaki
  7. Harry A T Pritchard
  8. Brant E Isakson
  9. Cam Ha T Tran
  10. Scott Earley  Is a corresponding author
  1. University of Nevada, Reno, United States
  2. University of Vermont, United States
  3. University of Arizona, Tucson, United States
  4. University of Manchester, United Kingdom
  5. University of Virginia, United States
Research Article
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Cite this article as: eLife 2021;10:e63040 doi: 10.7554/eLife.63040

Abstract

Cerebral blood flow is dynamically regulated by neurovascular coupling to meet the dynamic metabolic demands of the brain. We hypothesized that TRPA1 channels in capillary endothelial cells are stimulated by neuronal activity and instigate a propagating retrograde signal that dilates upstream parenchymal arterioles to initiate functional hyperemia. We find that activation of TRPA1 in capillary beds and post-arteriole transitional segments with mural cell coverage initiates retrograde signals that dilate upstream arterioles. These signals exhibit a unique mode of biphasic propagation. Slow, short-range intercellular Ca2+ signals in the capillary network are converted to rapid electrical signals in transitional segments that propagate to and dilate upstream arterioles. We further demonstrate that TRPA1 is necessary for functional hyperemia and neurovascular coupling within the somatosensory cortex of mice in vivo. These data establish endothelial cell TRPA1 channels as neuronal activity sensors that initiate microvascular vasodilatory responses to redirect blood to regions of metabolic demand.

Data availability

All data generated or analyzed during this study are included in the manuscript and supporting files. Source data files have been provided for all figures and figure supplements.

Article and author information

Author details

  1. Pratish Thakore

    Department of Pharmacology, School of Medicine, University of Nevada, Reno, Reno, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2086-5453
  2. Michael G Alvarado

    Department of Pharmacology, School of Medicine, University of Nevada, Reno, Reno, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3489-9021
  3. Sher Ali

    Department of Pharmacology, School of Medicine, University of Nevada, Reno, Reno, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Amreen Mughal

    Department of Pharmacology, College of Medicine, University of Vermont, Burlington, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0046-2286
  5. Paulo W Pires

    Department of Physiology, College of Medicine, University of Arizona, Tucson, Tucson, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5972-4554
  6. Evan Yamasaki

    Department of Pharmacology, School of Medicine, University of Nevada, Reno, Reno, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Harry A T Pritchard

    Institute of Cardiovascular Sciences, University of Manchester, Manchester, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  8. Brant E Isakson

    Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Cam Ha T Tran

    Department of Pharmacology, School of Medicine, University of Nevada, Reno, Reno, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Scott Earley

    Department of Pharmacology, School of Medicine, University of Nevada, Reno, Reno, United States
    For correspondence
    searley@med.unr.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9560-2941

Funding

National Heart, Lung, and Blood Institute (R01HL091905)

  • Scott Earley

National Institute of General Medical Sciences (P20GM130459)

  • Scott Earley

National Heart, Lung, and Blood Institute (R35HL155008)

  • Scott Earley

National Heart, Lung, and Blood Institute (R01HL137852)

  • Scott Earley

National Heart, Lung, and Blood Institute (R01HL139585)

  • Scott Earley

National Heart, Lung, and Blood Institute (R01HL146054)

  • Scott Earley

National Heart, Lung, and Blood Institute (K99HL140106)

  • Paulo W Pires

National Heart, Lung, and Blood Institute (P01HL120840)

  • Brant E Isakson

National Heart, Lung, and Blood Institute (R01HL137112)

  • Brant E Isakson

National Institute of Neurological Disorders and Stroke (RF1NS110044)

  • Scott Earley

National Institute of Neurological Disorders and Stroke (R61NS115132)

  • Scott Earley

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: All animal procedures used in this study were approved by the Institutional Animal Care and Use Committee of the University of Nevada, Reno, School of Medicine (protocol number: 20-06-1020).

Reviewing Editor

  1. Kenton J Swartz, National Institute of Neurological Disorders and Stroke, National Institutes of Health, United States

Publication history

  1. Received: September 11, 2020
  2. Accepted: February 25, 2021
  3. Accepted Manuscript published: February 26, 2021 (version 1)
  4. Version of Record published: March 5, 2021 (version 2)

Copyright

© 2021, Thakore et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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