SARS-CoV-2 triggers pericyte-mediated cerebral capillary constriction.
SARS-CoV-2 triggers pericyte-mediated cerebral capillary constriction.
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DOI：
10.1093/brain/awac272
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发表时间：
2023-02-13
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SARS-CoV-2受体ACE 2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。ACE 2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）。在仓鼠脑切片中，其具有与人类ACE 2相似的ACE 2序列，血管紧张素II通过AT 1受体引起小的周细胞介导的毛细血管收缩，但当SARS-CoV-2受体结合结构域（RBD，原始武汉变体）存在时引起大的收缩。突变的非结合RBD不增强收缩。类似的RBD增强毛细血管收缩发生在人类皮层切片，并诱发仓鼠脑切片的假型病毒体表达SARS-CoV-2刺突蛋白。这种收缩反映了RBD诱导的血管紧张素II转化为血管紧张素-（1-7）的减少，其通过从细胞表面膜去除ACE 2介导，并通过阻断ACE 2来模拟。临床使用的药物氯沙坦抑制RBD增强的收缩。因此，AT 1受体阻滞剂可以通过防止周细胞介导的大脑（可能还有心脏和肾脏）血流量减少来保护COVID-19。Hirunpartarasilp等人表明，SARS-CoV-2的结合使毛细血管周细胞上的ACE 2失活，导致周细胞收缩、毛细血管收缩和大脑（可能还有肾脏和心脏）中的血流量减少。一种常用的药物，氯沙坦，可以防止这些影响。关于这篇文章的科学评论，见Miners等人（https：//doi.org/10.1093/brain/awac481）。
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. Hirunpattarasilp et al. show that the binding of SARS-CoV-2 inactivates ACE2 on capillary pericytes, leading to pericyte contraction, capillary constriction and a reduction of blood flow in the brain (and possibly the kidney and heart). A commonly used drug, losartan, can prevent these effects. See Miners et al. (https://doi.org/10.1093/brain/awac481) for a scientific commentary on this article.
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