Vascular control of the CO2/H+ dependent drive to breathe
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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source data files are included for all data sets that do not have individual points on summary figures
Article and author information
Author details
Funding
National Institutes of Health (HL104101)
- Daniel K Mulkey
São 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 Longden
American Heart Association (19IPLOI34660108)
- Thomas Longden
São 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.
Reviewing Editor
- Jeffrey C Smith, National Institute of Neurological Disorders and Stroke, United States
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.
Version history
- Received: May 29, 2020
- Accepted: September 14, 2020
- Accepted Manuscript published: September 14, 2020 (version 1)
- Accepted Manuscript updated: September 16, 2020 (version 2)
- Version of Record published: September 28, 2020 (version 3)
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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