Journal
JOURNAL OF CLINICAL INVESTIGATION
Volume 132, Issue 9, Pages -Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI154118
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Funding
- Biotechnology and Biological Sciences Research Council London Interdisciplinary Biosciences Consortium PhD studentship
- British Heart Foundation (BHF)
- Wellcome Trust Oxion PhD studentship
- European Molecular Biology Organization Fellowship
- BHF Centre of Excellence [RE/18/4/34215]
- ERC Advanced Investigator Award (BrainEnergy)
- Wellcome Trust [099222/Z/12/Z, 219366/Z/19/Z]
- BHF [PG/19/8/34168]
- Olster Memorial Fund
- Physiological Society sabbatical Travel Grants
- Wellcome Trust [219366/Z/19/Z] Funding Source: Wellcome Trust
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A small increase in cytoplasmic calcium concentration in pericytes activates chloride efflux through the TMEM16A channel, leading to depolarization of the cell and opening of voltage-gated calcium channels. Inhibition of TMEM16A slows down ischemia-induced increase in calcium concentration, reduces pericyte death, and improves cerebrovascular reperfusion in a rodent stroke model. Altered TMEM16A expression is implicated in poor patient recovery from ischemic stroke, suggesting its potential as a therapeutic target.
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.
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