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

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.

Automated summary

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.