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

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+]Cai) 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+]Cai rise and capillary constriction evoked by contractile agonists and ischemia. In a rodent stroke model, TMEM16A inhibition slows the ischemia-evoked pericyte [Ca2+]Cai 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.

Identification of a 6-RBP gene signature for a comprehensive analysis of glioma and ischemic stroke: Cognitive impairment and aging-related hypoxic stress

“…Pericytes play an important role in regulating various microvascular functions, such as angiogenesis (Winkler et al, 2011 ), the formation and maintenance of the BBB (Armulik et al, 2010 ; Daneman et al, 2010 ), capillary blood flow regulation (Hall et al, 2014 ; Korte et al, 2022 ), neuroinflammatory regulation (Stark et al, 2013 ; Korte et al, 2022 ), glial plaque formation (Göritz et al, 2011 ), and stem cell characterization (Özen et al, 2014 ; Nakagomi et al, 2015 ). Pericytes are important therapeutic targets in stroke, glioma, Alzheimer's disease, spinal cord injury, and other diseases due to their vital role in the nervous system diseases (Cheng et al, 2018 ).…”

Neurovascular coupling mechanisms in health and neurovascular uncoupling in Alzheimer’s disease

“…Recent work has identified the TMEM16A channel, a Ca 2+ -activated chloride channel, as a mediator of pericyte depolarization and constriction. 149 It is hypothesized that a small rise in [Ca 2+ ] i (such as provoked by ET-1) could trigger chloride efflux via TMEM16A, depolarizing and constricting the pericyte. Supporting evidence comes from experiments showing that pharmacological inhibition as well as genetic knockout of TMEM16A channels reduces ET-1-evoked vasoconstriction, and that reducing [Cl – ] i abolishes this effect.…”

“…Supporting evidence comes from experiments showing that pharmacological inhibition as well as genetic knockout of TMEM16A channels reduces ET-1-evoked vasoconstriction, and that reducing [Cl – ] i abolishes this effect. Given that TMEM16A inhibition blocks pericyte contraction and thus improves CBF in an in vivo mouse model of stroke, 149 future work should aim to elucidate if TMEM16A plays a role in NVC and if its blockade can prevent the NVC deficits caused by Aβ-dependent ET-1 release mentioned above. 92 …”

The role of the astrocyte in subarachnoid hemorrhage and its therapeutic implications

“…Delayed cerebral ischemia after SAH results in severe functional and cognitive deficits, which are due to vasospasm caused mainly by the abnormal constriction of pericytes ( 106 , 107 ). Although there are studies concerning Ca 2+ -related pericyte constrictions in other neurological disorders, such as ischemic stroke ( 108 , 109 ), evidence regarding how astrocytes regulate pericyte constrictions following SAH is still insufficient and thus remains to be further explored.…”