The Ca2+-gated channel TMEM16A amplifies capillary pericyte contraction and reduces cerebral blood flow after ischemia.
The Ca2+-gated channel TMEM16A amplifies capillary pericyte contraction and reduces cerebral blood flow after ischemia.
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DOI：
10.1172/jci154118
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发表时间：
2022-05-02
影响因子：
15.9
通讯作者：
Tammaro, Paolo
中科院分区：
文献类型：
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作者：
Korte, Nils;Ilkan, Zeki;Pearson, Claire L.;Pfeiffer, Thomas;Singhal, Prabhav;Rock, Jason R.;Sethi, Huma;Gill, Dipender;Attwell, David;Tammaro, Paolo
闭塞动脉疏通后，周细胞介导的毛细血管收缩减少了中风患者的脑血流量。周细胞张力的决定因素知之甚少。我们发现，在周细胞胞浆Ca 2+浓度（[Ca 2 +]i）的小幅上升激活氯离子流出通过Ca 2+门控阴离子通道TMEM 16 A，从而去极化细胞和开放电压门控钙通道。这种机制强烈放大了由收缩激动剂和缺血引起的周细胞[Ca 2 +]i升高和毛细血管收缩。在啮齿动物中风模型中，TMEM 16 A抑制减缓了缺血诱发的周细胞[Ca 2 +]i升高、毛细血管收缩和周细胞死亡;减少了中性粒细胞停滞;并改善了脑血管再灌注。遗传分析表明TMEM 16 A表达改变与缺血性卒中患者恢复不良有关。因此，周细胞TMEM 16 A是脑毛细血管功能的重要调节剂，并且是中风和可能的其他微血管流动受损的病症（例如阿尔茨海默病和血管性痴呆）的潜在治疗靶标。
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 Ca2+-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.