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

被引：79

作者：

Korte, Nils ^{[1
]}

Ilkan, Zeki ^{[2
]}

Pearson, Claire L. ^{[2
]}

Pfeiffer, Thomas ^{[1
]}

Singhal, Prabhav ^{[1
]}

Rock, Jason R. ^{[3
]}

Sethi, Huma ^{[4
]}

Gill, Dipender ^{[5
]}

Attwell, David ^{[1
]}

Tammaro, Paolo ^{[2
]}

机构：

[1] UCL, Dept Neurosci Physiol & Pharmacol, Gower St, London, England

[2] Univ Oxford, Dept Pharmacol, Mansfield Rd, Oxford, England

[3] Boston Univ, Ctr Regenerat Med, Sch Med, Boston, MA USA

[4] Natl Hosp Neurol & Neurosurg, Dept Neurosurg, London, England

[5] Imperial Coll London, Dept Epidemiol & Biostat, St Marys Hosp, London, England

来源：

JOURNAL OF CLINICAL INVESTIGATION | 2022年 / 132卷 / 09期

基金：

英国惠康基金; 英国生物技术与生命科学研究理事会;

关键词：

CL-CHANNELS; BRAIN; PRESSURE; DIAMETER; REPERFUSION; PHENOTYPE; NETWORK; PROTEIN; STROKE; REFLOW;

D O I：

10.1172/JCI154118

中图分类号：

R-3 [医学研究方法]; R3 [基础医学];

学科分类号：

1001 ;

摘要：

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 activated chloride efflux through the Cat'-gated anion channel TMEM16A, thus depolarizing the cell and opening voltage-gated calcium channels. This mechanism strongly amplified the pericyte [Ca2+](i) rise and capillary constriction evoked by contractile agonists and ischemia. In a rodent stroke model, TMEM16A inhibition slowed the ischemia-evoked pericyte [Ca2+](i) rise, capillary constriction, and pericyte death; reduced neutrophil stalling; and improved cerebrovascular reperfusion. Genetic analysis implicated 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.

引用

页数：17

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