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

Hirunpattarasilp, C.; James, G.; Freitas, F.; Sethi, H.; Kittler, J. T.; Huo, J.; Owens, R. J.; Attwell, D.

doi:10.1101/2021.04.01.438122

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bioRxiv · 10.1101/2021.04.01.438122

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

Hirunpattarasilp, C.·James, G.·Freitas, F.·Sethi, H.·Kittler, J. T.·Huo, J.·Owens, R. J.·Attwell, D.

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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.

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Hirunpattarasilp, C., James, G., Freitas, F., Sethi, H., Kittler, J. T., Huo, J., Owens, R. J., Attwell, D.. 2021-04-01. SARS-CoV-2 binding to ACE2 triggers pericyte-mediated angiotensin-evoked cerebral capillary constriction. https://doi.org/10.1101/2021.04.01.438122

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