Korte, Nils;
Ilkan, Zeki;
Pearson, Claire L;
Pfeiffer, Thomas;
Singhal, Prabhav;
Rock, Jason R;
Sethi, Huma;
... Tammaro, Paolo; + view all
(2022)
The Ca²⁺-gated channel TMEM16A amplifies capillary pericyte contraction and reduces cerebral blood flow after ischemia.
The Journal of Clinical Investigation
10.1172/JCI154118.
(In press).
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Abstract
Pericyte-mediated capillary constriction decreases cerebral blood flow in stroke after an occluded artery is unblocked. The determinants of pericyte tone are poorly understood. We show that a small rise in cytoplasmic Ca2+ concentration ([Ca2+]i) in pericytes activates chloride efflux through the Ca2+-gated anion channel TMEM16A, thus depolarizing the cell and opening voltage-gated calcium channels. This mechanism strongly amplifies the pericyte [Ca2+]i rise and capillary constriction evoked by contractile agonists and ischemia. In a rodent stroke model, TMEM16A inhibition slows the ischemia-evoked pericyte [Ca2+]i rise, capillary constriction and pericyte death, reduces neutrophil stalling and improves cerebrovascular reperfusion. Genetic analysis implicates altered TMEM16A expression in poor patient recovery from ischemic stroke. Thus, pericyte TMEM16A is a crucial regulator of cerebral capillary function, and a potential therapeutic target for stroke and possibly other disorders of impaired microvascular flow, such as Alzheimer’s disease and vascular dementia.
| Type: | Article |
|---|---|
| Title: | The Ca²⁺-gated channel TMEM16A amplifies capillary pericyte contraction and reduces cerebral blood flow after ischemia |
| Location: | United States |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1172/JCI154118 |
| Publisher version: | https://doi.org/10.1172/JCI154118 |
| Language: | English |
| Additional information: | This is an Open Access article published under a Creative Commons Attribution 4.0 International (CC BY 4.0) Licence (https://creativecommons.org/licenses/by/4.0/). |
| Keywords: | TMEM16A, pericyte, ischemic stroke, capillary physiology, microcirculation, ion channels, calcium signalling |
| UCL classification: | UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Neuro, Physiology and Pharmacology UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10146626 |
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