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SARS-CoV-2 triggers pericyte-mediated cerebral capillary constriction
Brain ( IF 10.6 ) Pub Date : 2022-07-22 , DOI: 10.1093/brain/awac272
Chanawee Hirunpattarasilp 1, 2 , Greg James 1, 3 , Jaturon Kwanthongdee 1, 2 , Felipe Freitas 1 , Jiandong Huo 4, 5 , Huma Sethi 6 , Josef T Kittler 1 , Raymond J Owens 4, 5 , Laura E McCoy 7 , David Attwell 1
Affiliation  

The SARS-CoV-2 receptor, ACE2, is found on pericytes, contractile cells enwrapping capillaries that regulate brain, heart and kidney blood flow. ACE2 converts vasoconstricting angiotensin II into vasodilating angiotensin-(1-7). In brain slices from hamster, which has an ACE2 sequence similar to human ACE2, angiotensin II evoked a small pericyte-mediated capillary constriction via AT1 receptors, but evoked a large constriction when the SARS-CoV-2 receptor binding domain (RBD, original Wuhan variant) was present. A mutated non-binding RBD did not potentiate constriction. A similar RBD-potentiated capillary constriction occurred in human cortical slices, and was evoked in hamster brain slices by pseudotyped virions expressing SARS-CoV-2 spike protein. This constriction reflects an RBD-induced decrease in the conversion of angiotensin II to angiotensin-(1-7) mediated by removal of ACE2 from the cell surface membrane, and was mimicked by blocking ACE2. The clinically-used drug losartan inhibited the RBD-potentiated constriction. Thus, AT1 receptor blockers could be protective in Covid-19 by preventing pericyte-mediated blood flow reductions in the brain, and perhaps the heart and kidney.

中文翻译:


SARS-CoV-2 触发周细胞介导的脑毛细血管收缩



SARS-CoV-2 受体 ACE2 存在于周细胞上,周细胞是包裹毛细血管的收缩细胞,可调节大脑、心脏和肾脏的血流。 ACE2 将血管收缩性血管紧张素 II 转化为血管舒张性血管紧张素-(1-7)。在仓鼠的脑切片中,其 ACE2 序列与人类 ACE2 相似,血管紧张素 II 通过 AT1 受体引起周细胞介导的小毛细血管收缩,但当 SARS-CoV-2 受体结合域(RBD,原武汉变体)存在。突变的非结合 RBD 不会增强收缩。类似的 RBD 增强的毛细血管收缩发生在人类皮质切片中,并在仓鼠脑切片中由表达 SARS-CoV-2 刺突蛋白的假型病毒体引起。这种收缩反映了 RBD 诱导的血管紧张素 II 向血管紧张素-(1-7) 转化的减少,这是通过从细胞表面膜去除 ACE2 介导的,并且通过阻断 ACE2 来模拟。临床使用的药物氯沙坦可抑制 RBD 增强的收缩。因此,AT1 受体阻滞剂可以通过防止大脑(或许还有心脏和肾脏)周细胞介导的血流量减少来对 Covid-19 起到保护作用。
更新日期:2022-07-22
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