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Brain Endothelial Cell TRPA1 Channels Initiate Neurovascular Coupling

View ORCID ProfilePratish Thakore, Michael G. Alvarado, Sher Ali, Amreen Mughal, Paulo W. Pires, View ORCID ProfileEvan Yamasaki, View ORCID ProfileHarry A. T. Pritchard, Brant E. Isakson, Cam Ha T. Tran, View ORCID ProfileScott Earley
doi: https://doi.org/10.1101/2020.09.14.295600
Pratish Thakore
1Department of Pharmacology, Center for Molecular and Cellular Signaling in the Cardiovascular System, University of Nevada, Reno School of Medicine, Reno, NV 8957-0318, USA
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Michael G. Alvarado
1Department of Pharmacology, Center for Molecular and Cellular Signaling in the Cardiovascular System, University of Nevada, Reno School of Medicine, Reno, NV 8957-0318, USA
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Sher Ali
1Department of Pharmacology, Center for Molecular and Cellular Signaling in the Cardiovascular System, University of Nevada, Reno School of Medicine, Reno, NV 8957-0318, USA
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Amreen Mughal
2Department of Pharmacology, College of Medicine, University of Vermont, Burlington, VT 05405, USA
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Paulo W. Pires
3Department of Physiology, College of Medicine, University of Arizona, Tucson, AZ 85724, USA
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Evan Yamasaki
1Department of Pharmacology, Center for Molecular and Cellular Signaling in the Cardiovascular System, University of Nevada, Reno School of Medicine, Reno, NV 8957-0318, USA
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Harry A. T. Pritchard
1Department of Pharmacology, Center for Molecular and Cellular Signaling in the Cardiovascular System, University of Nevada, Reno School of Medicine, Reno, NV 8957-0318, USA
4Institute of Cardiovascular Sciences, University of Manchester, M13 9PL Manchester, United Kingdom
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Brant E. Isakson
5Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, VA 22908, USA
6Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville, VA 22908, USA
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Cam Ha T. Tran
7Department of Physiology & Cell Biology, Center for Molecular and Cellular Signaling in the Cardiovascular System, University of Nevada, Reno School of Medicine, Reno, NV 8957-0318, USA
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Scott Earley
1Department of Pharmacology, Center for Molecular and Cellular Signaling in the Cardiovascular System, University of Nevada, Reno School of Medicine, Reno, NV 8957-0318, USA
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  • For correspondence: searley@med.unr.edu
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Abstract

Blood flow regulation in the brain is dynamically regulated to meet the metabolic demands of active neuronal populations. Recent evidence has demonstrated that capillary endothelial cells are essential mediators of neurovascular coupling that sense neuronal activity and generate a retrograde, propagating, hyperpolarizing signal that dilates upstream arterioles. Here, we tested the hypothesis that transient receptor potential ankyrin 1 (TRPA1) channels in capillary endothelial cells are significant contributors to functional hyperemic responses that underlie neurovascular coupling in the brain. Using an integrative ex vivo and in vivo approach, we demonstrate the functional presence of TRPA1 channels in brain capillary endothelial cells, and show that activation of these channels within the capillary bed, including the post-arteriole transitional region covered by ensheathing mural cells, initiates a retrograde signal that dilates upstream parenchymal arterioles. Notably, this signaling exhibits a unique biphasic mode of propagation that begins within the capillary network as a short-range, Ca2+ signal dependent on endothelial pannexin-1 channel/purinergic P2X receptor communication pathway and then is converted to a rapid, inward-rectifying K+ channel-mediated electrical signal in the post-arteriole transitional region that propagates upstream to parenchymal arterioles. Two-photon laser-scanning microscopy further demonstrated that conductive vasodilation occurs in vivo, and that TRPA1 is necessary for functional hyperemia within the somatosensory cortex of mice. Together, these data establish a role for endothelial TRPA1 channels as sensors of neuronal activity and show that they respond accordingly by initiating a vasodilatory response that redirects blood to regions of metabolic demand.

Competing Interest Statement

The authors have declared no competing interest.

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Brain Endothelial Cell TRPA1 Channels Initiate Neurovascular Coupling
Pratish Thakore, Michael G. Alvarado, Sher Ali, Amreen Mughal, Paulo W. Pires, Evan Yamasaki, Harry A. T. Pritchard, Brant E. Isakson, Cam Ha T. Tran, Scott Earley
bioRxiv 2020.09.14.295600; doi: https://doi.org/10.1101/2020.09.14.295600
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Brain Endothelial Cell TRPA1 Channels Initiate Neurovascular Coupling
Pratish Thakore, Michael G. Alvarado, Sher Ali, Amreen Mughal, Paulo W. Pires, Evan Yamasaki, Harry A. T. Pritchard, Brant E. Isakson, Cam Ha T. Tran, Scott Earley
bioRxiv 2020.09.14.295600; doi: https://doi.org/10.1101/2020.09.14.295600

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