Neuroprotective effects of TRPA1 channels in the cerebral endothelium following ischemic stroke

  1. Paulo Wagner Pires
  2. Scott Earley  Is a corresponding author
  1. University of Nevada, Reno School of Medicine, United States

Abstract

Hypoxia and ischemia are linked to oxidative stress, which can activate the oxidant-sensitive transient receptor potential ankyrin 1 (TRPA1) channel in cerebral artery endothelial cells, leading to vasodilation. We hypothesized that TRPA1 channels in endothelial cells are activated by hypoxia-derived reactive oxygen species, leading to cerebral artery dilation and reduced ischemic damage. Using isolated cerebral arteries expressing a Ca2+ biosensor in endothelial cells, we show that 4-hydroxynonenal and hypoxia increased TRPA1 activity, detected as TRPA1 sparklets. TRPA1 activity during hypoxia was blocked by antioxidants and by TRPA1 antagonism. Hypoxia caused dilation of cerebral arteries, which was disrupted by antioxidants, TRPA1 blockade and by endothelial cell-specific Trpa1 deletion (Trpa1 ecKO mice). Loss of TRPA1 channels in endothelial cells increased cerebral infarcts, whereas TRPA1 activation with cinnamaldehyde reduced infarct in wildtype, but not Trpa1 ecKO, mice. These data suggest that endothelial TRPA1 channels are sensors of hypoxia leading to vasodilation, thereby reducing ischemic damage.

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 Figures 1 - 8 and Supplemental Figures 2,3,5,6,7,8,9 and 10.

Article and author information

Author details

  1. Paulo Wagner Pires

    Department of Pharmacology, University of Nevada, Reno School of Medicine, Reno, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5972-4554
  2. Scott Earley

    University of Nevada, Reno School of Medicine, University of Nevada, Reno School of Medicine, 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)

  • Paulo Wagner Pires
  • Scott Earley

American Heart Association (15POST2472002)

  • Paulo Wagner Pires

National Heart, Lung, and Blood Institute (K99HL140106)

  • Paulo Wagner Pires
  • 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 (IACUC protocol #2016-00598), and are in accordance with the National Institutes of Health 'Guide for the Care and Use of Laboratory Animals', 8th edition.

Reviewing Editor

  1. David Kleinfeld, University of California, San Diego, United States

Publication history

  1. Received: January 25, 2018
  2. Accepted: September 18, 2018
  3. Accepted Manuscript published: September 21, 2018 (version 1)
  4. Version of Record published: October 9, 2018 (version 2)

Copyright

© 2018, Pires & Earley

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. Paulo Wagner Pires
  2. Scott Earley
(2018)
Neuroprotective effects of TRPA1 channels in the cerebral endothelium following ischemic stroke
eLife 7:e35316.
https://doi.org/10.7554/eLife.35316

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