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SARS-CoV-2 binding to ACE2 triggers pericyte-mediated angiotensin-evoked cerebral capillary constriction

View ORCID ProfileChanawee Hirunpattarasilp, Gregory James, View ORCID ProfileFelipe Freitas, Huma Sethi, View ORCID ProfileJosef T. Kittler, Jiandong Huo, View ORCID ProfileRaymond J. Owens, View ORCID ProfileDavid Attwell
doi: https://doi.org/10.1101/2021.04.01.438122
Chanawee Hirunpattarasilp
1Department of Neuroscience, Physiology & Pharmacology, University College London, Gower Street, London, WC1E 6BT, UK
2HRH Princess Chulabhorn College of Medical Science, Chulabhorn Royal Academy, 906 Kamphaeng Phet 6 Rd, Talat Bang Khen, Lak Si, Bangkok 10210, Thailand
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Gregory James
1Department of Neuroscience, Physiology & Pharmacology, University College London, Gower Street, London, WC1E 6BT, UK
3Department of Neurosurgery, Great Ormond Street Hospital, London, WC1N 3JH, UK
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Felipe Freitas
1Department of Neuroscience, Physiology & Pharmacology, University College London, Gower Street, London, WC1E 6BT, UK
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Huma Sethi
4National Hospital for Neurology and Neurosurgery, Queen Square, London, WC1N 3BG, UK
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Josef T. Kittler
1Department of Neuroscience, Physiology & Pharmacology, University College London, Gower Street, London, WC1E 6BT, UK
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Jiandong Huo
5Division of Structural Biology, Nuffield Department of Medicine, University of Oxford, OX3 7BN, UK
6Protein Production UK, The Research Complex at Harwell, and Rosalind Franklin Institute, Harwell Science & Innovation Campus, Didcot, OX11 0GD, UK
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Raymond J. Owens
5Division of Structural Biology, Nuffield Department of Medicine, University of Oxford, OX3 7BN, UK
6Protein Production UK, The Research Complex at Harwell, and Rosalind Franklin Institute, Harwell Science & Innovation Campus, Didcot, OX11 0GD, UK
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David Attwell
1Department of Neuroscience, Physiology & Pharmacology, University College London, Gower Street, London, WC1E 6BT, UK
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  • For correspondence: d.attwell@ucl.ac.uk
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Abstract

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 alone evoked only a small capillary constriction, but evoked a large pericyte-mediated capillary constriction generated by AT1 receptors in the presence of the SARS-CoV-2 receptor binding domain (RBD). The effect of the RBD was mimicked by blocking ACE2. A mutated non-binding RBD did not potentiate constriction. A similar RBD-potentiated capillary constriction occurred in human cortical slices. This constriction reflects an RBD-induced decrease in the conversion of angiotensin II to angiotensin-(1-7). The clinically-used drug losartan inhibited the RBD-potentiated constriction. Thus AT1 receptor blockers could be protective in SARS-CoV-2 infection by reducing pericyte-mediated blood flow reductions in the brain, and perhaps the heart and kidney.

Competing Interest Statement

The authors have declared no competing interest.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted April 01, 2021.
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SARS-CoV-2 binding to ACE2 triggers pericyte-mediated angiotensin-evoked cerebral capillary constriction
Chanawee Hirunpattarasilp, Gregory James, Felipe Freitas, Huma Sethi, Josef T. Kittler, Jiandong Huo, Raymond J. Owens, David Attwell
bioRxiv 2021.04.01.438122; doi: https://doi.org/10.1101/2021.04.01.438122
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SARS-CoV-2 binding to ACE2 triggers pericyte-mediated angiotensin-evoked cerebral capillary constriction
Chanawee Hirunpattarasilp, Gregory James, Felipe Freitas, Huma Sethi, Josef T. Kittler, Jiandong Huo, Raymond J. Owens, David Attwell
bioRxiv 2021.04.01.438122; doi: https://doi.org/10.1101/2021.04.01.438122

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