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

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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.

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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.

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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.

"This ORCID iD identifies the author of this article:" 0000-0001-5972-4554
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.

"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.

Copyright

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.