1. Neuroscience

Vascular control of the CO2/H+ dependent drive to breathe

  1. Colin M Cleary
  2. Thiago S Moreira
  3. Ana C Takakura
  4. Mark T Nelson
  5. Thomas A Longden
  6. Daniel K Mulkey  Is a corresponding author
  1. University of Connecticut, United States
  2. University of São Paulo, Brazil
  3. University of Vermont, United States
  4. University of Maryland, United States
https://doi.org/10.7554/eLife.59499
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  1. Colin M Cleary
  2. Thiago S Moreira
  3. Ana C Takakura
  4. Mark T Nelson
  5. Thomas A Longden
  6. Daniel K Mulkey
(2020)
Vascular control of the CO2/H+ dependent drive to breathe
eLife 9:e59499.
https://doi.org/10.7554/eLife.59499
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Abstract

Respiratory chemoreceptors regulate breathing in response to changes in tissue CO2/H+. Blood flow is a fundamental determinant of tissue CO2/H+, yet little is known regarding how regulation of vascular tone in chemoreceptor regions contributes to respiratory behavior. Previously, we showed in rat that CO2/H+-vasoconstriction in the retrotrapezoid nucleus (RTN) supports chemoreception by a purinergic-dependent mechanism (Hawkins et al. 2017). Here, we show in mice that CO2/H+ dilates arterioles in other chemoreceptor regions, thus demonstrating CO2/H+ vascular reactivity in the RTN is unique. We also identify P2Y2 receptors in RTN smooth muscle cells as the substrate responsible for this response. Specifically, pharmacological blockade or genetic deletion of P2Y2 from smooth muscle cells blunted the ventilatory response to CO2, and re-expression of P2Y2 receptors only in RTN smooth muscle cells fully rescued the CO2/H+ chemoreflex. These results identify P2Y2 receptors in RTN smooth muscle cells as requisite determinants of respiratory chemoreception.

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Author details

  1. Colin M Cleary

    Department of Physiology and Neurobiology, University of Connecticut, Storrs, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0305-1324

  2. Thiago S Moreira

    Department of Physiology and Biophysics, University of São Paulo, São Paulo, Brazil
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9789-8296

  3. Ana C Takakura

    Department of Pharmacology, University of São Paulo, São Paulo, Brazil
    Competing interests
    No competing interests declared.

  4. Mark T Nelson

    Department of Pharmacology, University of Vermont, Burlington, United States
    Competing interests
    Mark T Nelson, Reviewing editor, eLife.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6608-8784

  5. Thomas A Longden

    Department of Physiology, University of Maryland, Baltimore, United States
    Competing interests
    No competing interests declared.

  6. Daniel K Mulkey

    Department of Physiology and Neurobiology, University of Connecticut, Storrs, United States
    For correspondence
    daniel.mulkey@uconn.edu
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7040-3927

Funding

National Institutes of Health (HL104101)

  • Daniel K Mulkey

Sao Paulo Research Foundation (2015/23376-1)

  • Thiago S Moreira

Conselho Nacional de Desenvolvimento Científico e Tecnológico (408647/2018-3)

  • Ana C Takakura

Conselho Nacional de Desenvolvimento Científico e Tecnológico (301219/2016-8)

  • Ana C Takakura

Conselho Nacional de Desenvolvimento Científico e Tecnológico (301904/2015-4)

  • Thiago S Moreira

Fondation Leducq

  • Mark T Nelson

European Union Horizon 2020 Research and Innovation Programme

  • Mark T Nelson

Henry M. Jackson Foundation (HU0001-18-2-001)

  • Mark T Nelson

National Institutes of Health (HL137094)

  • Daniel K Mulkey

National Institutes of Health (NS099887)

  • Daniel K Mulkey

National Institutes of Health (NS110656)

  • Mark T Nelson

National Institutes of Health (HL140027)

  • Mark T Nelson

National Institutes of Health (HL142227)

  • Colin M Cleary

American Heart Association (17SDG33670237)

  • Thomas A Longden

American Heart Association (19IPLOI34660108)

  • Thomas A Longden

Sao Paulo Research Foundation (2016/23281-3)

  • Ana C Takakura

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 procedures were performed in accordance with National Institutes of Health and University of Connecticut Animal Care and Use Guidelines as described in protocols A19-048 and A20-016.

Copyright

© 2020, Cleary 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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  1. Colin M Cleary
  2. Thiago S Moreira
  3. Ana C Takakura
  4. Mark T Nelson
  5. Thomas A Longden
  6. Daniel K Mulkey
(2020)
Vascular control of the CO2/H+ dependent drive to breathe
eLife 9:e59499.
https://doi.org/10.7554/eLife.59499

Share this article

https://doi.org/10.7554/eLife.59499

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Further reading

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    Purinergic regulation of vascular tone in the retrotrapezoid nucleus is specialized to support the drive to breathe

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    Cerebral blood flow is highly sensitive to changes in CO2/H+ where an increase in CO2/H+ causes vasodilation and increased blood flow. Tissue CO2/H+ also functions as the main stimulus for breathing by activating chemosensitive neurons that control respiratory output. Considering that CO2/H+-induced vasodilation would accelerate removal of CO2/H+ and potentially counteract the drive to breathe, we hypothesize that chemosensitive brain regions have adapted a means of preventing vascular CO2/H+-reactivity. Here, we show in rat that purinergic signaling, possibly through P2Y2/4 receptors, in the retrotrapezoid nucleus (RTN) maintains arteriole tone during high CO2/H+ and disruption of this mechanism decreases the CO2ventilatory response. Our discovery that CO2/H+-dependent regulation of vascular tone in the RTN is the opposite to the rest of the cerebral vascular tree is novel and fundamentally important for understanding how regulation of vascular tone is tailored to support neural function and behavior, in this case the drive to breathe.

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