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Publication Detail
The Ca²⁺-gated channel TMEM16A amplifies capillary pericyte contraction and reduces cerebral blood flow after ischemia
  • Publication Type:
    Journal article
  • Authors:
    Korte N, Ilkan Z, Pearson CL, Pfeiffer T, Singhal P, Rock JR, Sethi H, Gill D, Attwell D, Tammaro P
  • Publisher:
    American Society for Clinical Investigation
  • Publication date:
    22/03/2022
  • Journal:
    The Journal of Clinical Investigation
  • Medium:
    Print-Electronic
  • Status:
    Accepted
  • Country:
    United States
  • PII:
    154118
  • Language:
    English
  • Keywords:
    TMEM16A, pericyte, ischemic stroke, capillary physiology, microcirculation, ion channels, calcium signalling
  • Notes:
    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/).
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.
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