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bioRxiv · 10.1101/2022.02.03.479031

The Ca2+-gated Cl- channel TMEM16A amplifies capillary pericyte contraction reducing cerebral blood flow after ischemia

Korte, N.·Ilkan, Z.·Pearson, C.·Pfeiffer, T.·Singhal, P.·Rock, J.·Sethi, H.·Gill, D.·Attwell, D.·Tammaro, P.
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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 Alzheimers disease and vascular dementia.

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Korte, N., Ilkan, Z., Pearson, C., Pfeiffer, T., Singhal, P., Rock, J., Sethi, H., Gill, D., Attwell, D., Tammaro, P.. 2022-02-05. The Ca2+-gated Cl- channel TMEM16A amplifies capillary pericyte contraction reducing cerebral blood flow after ischemia. https://doi.org/10.1101/2022.02.03.479031

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