Brain endothelial cell TRPA1 channels initiate neurovascular coupling
- University of Nevada, Reno, United States
- University of Vermont, United States
- University of Arizona, Tucson, United States
- University of Manchester, United Kingdom
- University of Virginia, United States
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
Michael G Alvarado
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).
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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Brain endothelial cell TRPA1 channels initiate neurovascular coupling
eLife 10:e63040.
https://doi.org/10.7554/eLife.63040
