SARS-CoV-2 triggers pericyte-mediated cerebral capillary constriction

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 huma...

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Bibliographic Details
Published in:Brain (London, England : 1878) England : 1878), 2023-02, Vol.146 (2), p.727-738
Main Authors: Hirunpattarasilp, Chanawee, James, Greg, Kwanthongdee, Jaturon, Freitas, Felipe, Huo, Jiandong, Sethi, Huma, Kittler, Josef T, Owens, Raymond J, McCoy, Laura E, Attwell, David
Format: Article
Language:English
Subjects:
Angiotensin II - metabolism
Angiotensin II - pharmacology
Angiotensin-Converting Enzyme 2 - chemistry
Angiotensin-Converting Enzyme 2 - metabolism
Capillaries
Constriction
COVID-19 - metabolism
Humans
Original
Peptidyl-Dipeptidase A - genetics
Peptidyl-Dipeptidase A - metabolism
Pericytes - metabolism
Protein Binding
Receptors, Virus - chemistry
Receptors, Virus - metabolism
SARS-CoV-2 - metabolism
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Summary: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.
ISSN:0006-8950
1460-2156
DOI:10.1093/brain/awac272