Cerebral blood flow (CBF) is exquisitely controlled to meet the ever-changing demands of active neurons in the brain. Brain capillaries are equipped with sensors of neurovascular coupling agents released from neurons/astrocytes onto the outer wall of a capillary. While capillaries can translate external signals into electrical and Ca2+ changes, control mechanisms from the lumen are less clear. The continuous flux of red blood cells and plasma through narrow-diameter capillaries imposes mechanical forces on the luminal (inner) capillary wall. Whether—and, if so, how—the ever-changing CBF could be mechanically sensed in capillaries is not known. Here, we propose and provide evidence that the mechanosensitive Piezo1 channels operate as mechanosensors in CNS capillaries to ultimately regulate CBF. Patch clamp electrophysiology confirmed the expression and function of Piezo1 channels in brain cortical and retinal capillary endothelial cells. Mechanical or pharmacological activation of Piezo1 channels evoked currents that were sensitive to Piezo1 channel blockers. Using genetically encoded Ca2+ indicator (Cdh5-GCaMP8) mice, we observed that Piezo1 channel activation triggered Ca2+ signals in endothelial cells. An ex vivo pressurized retina preparation was employed to further explore the mechanosensitivity of capillary Piezo1-mediated Ca2+ signals. Genetic and pharmacologic manipulation of Piezo1 in endothelial cells had significant impacts on CBF, reemphasizing the crucial role of mechanosensation in blood flow control. In conclusion, this study shows that Piezo1 channels act as mechanosensors in capillaries, and that these channels initiate crucial Ca2+ signals. We further show that Piezo1 modulates CBF, an observation of profound significance for the control of brain blood flow in health and in disorders where hemodynamic forces are disrupted, such as hypertension.
Meeting Abstract|
E–C Coupling Meeting 2021|
November 12 2021
Piezo1 is a mechanosensor channel in CNS capillaries: Calcium Signaling and Excitation–Contraction in Cardiac, Skeletal and Smooth Muscle
Osama F. Harraz,
Osama F. Harraz
1Department of Pharmacology and Vermont Center for Cardiovascular and Brain Health, University of Vermont, Burlington, VT
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Nicholas R. Klug,
Nicholas R. Klug
1Department of Pharmacology and Vermont Center for Cardiovascular and Brain Health, University of Vermont, Burlington, VT
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Amanda Senatore,
Amanda Senatore
1Department of Pharmacology and Vermont Center for Cardiovascular and Brain Health, University of Vermont, Burlington, VT
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Masayo Koide,
Masayo Koide
1Department of Pharmacology and Vermont Center for Cardiovascular and Brain Health, University of Vermont, Burlington, VT
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Mark T. Nelson
Mark T. Nelson
1Department of Pharmacology and Vermont Center for Cardiovascular and Brain Health, University of Vermont, Burlington, VT
2Division of Cardiovascular Sciences, University of Manchester, Manchester, UK
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Osama F. Harraz
1Department of Pharmacology and Vermont Center for Cardiovascular and Brain Health, University of Vermont, Burlington, VT
Nicholas R. Klug
1Department of Pharmacology and Vermont Center for Cardiovascular and Brain Health, University of Vermont, Burlington, VT
Amanda Senatore
1Department of Pharmacology and Vermont Center for Cardiovascular and Brain Health, University of Vermont, Burlington, VT
Masayo Koide
1Department of Pharmacology and Vermont Center for Cardiovascular and Brain Health, University of Vermont, Burlington, VT
Mark T. Nelson
1Department of Pharmacology and Vermont Center for Cardiovascular and Brain Health, University of Vermont, Burlington, VT
2Division of Cardiovascular Sciences, University of Manchester, Manchester, UK
Online ISSN: 1540-7748
Print ISSN: 0022-1295
© 2021 Harraz et al.
2021
This article is available under a Creative Commons License (Attribution–Noncommercial–Share
Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).
J Gen Physiol (2022) 154 (9): e2021ecc12.
Citation
Osama F. Harraz, Nicholas R. Klug, Amanda Senatore, Masayo Koide, Mark T. Nelson; Piezo1 is a mechanosensor channel in CNS capillaries: Calcium Signaling and Excitation–Contraction in Cardiac, Skeletal and Smooth Muscle. J Gen Physiol 5 September 2022; 154 (9): e2021ecc12. doi: https://doi.org/10.1085/jgp.2021ecc12
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