SARS-CoV-2 binding to ACE2 triggers pericyte-mediated angiotensin-evoked cerebral capillary constriction
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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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SciScore for 10.1101/2021.04.01.438122: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement Consent: Ethical approval was obtained (REC number 15/NW/0568, IRAS ID 180727 (v3.0), “Properties of human pericytes”, as approved on 9-10-2018 for extension and amendment) and all patients gave informed written consent. Randomization not detected. Blinding not detected. Power Analysis not detected. Sex as a biological variable The constriction evoked by angiotensin II in the presence of the RBD showed overlapping ranges of value for 2 female vessels and 9 male vessels (p=0.67). Table 2: Resources
Antibodies Sentences Resources Primary antibodies used were goat anti-ACE2 (R&D systems, AF933, 1:200) anti-ACE2suggested: NoneSecondary antibodies used were Alexa fluor 488 donkey … SciScore for 10.1101/2021.04.01.438122: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement Consent: Ethical approval was obtained (REC number 15/NW/0568, IRAS ID 180727 (v3.0), “Properties of human pericytes”, as approved on 9-10-2018 for extension and amendment) and all patients gave informed written consent. Randomization not detected. Blinding not detected. Power Analysis not detected. Sex as a biological variable The constriction evoked by angiotensin II in the presence of the RBD showed overlapping ranges of value for 2 female vessels and 9 male vessels (p=0.67). Table 2: Resources
Antibodies Sentences Resources Primary antibodies used were goat anti-ACE2 (R&D systems, AF933, 1:200) anti-ACE2suggested: NoneSecondary antibodies used were Alexa fluor 488 donkey anti-goat (Invitrogen, A11055, 1:500) anti-goatsuggested: (Thermo Fisher Scientific Cat# A-11055, RRID:AB_2534102)A11055suggested: (Thermo Fisher Scientific Cat# A-11055, RRID:AB_2534102)Software and Algorithms Sentences Resources Diameter was measured in ImageJ by drawing a line across the vessel between the inner walls of the endothelial cells. ImageJsuggested: (ImageJ, RRID:SCR_003070)Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).
Results from LimitationRecognizer: An explicit section about the limitations of the techniques employed in this study was not found. We encourage authors to address study limitations.Results from TrialIdentifier: We found the following clinical trial numbers in your paper:
Identifier Status Title NCT04312009 Completed Losartan for Patients With COVID-19 Requiring Hospitalizatio… NCT04311177 Completed Losartan for Patients With COVID-19 Not Requiring Hospitaliz… Results from Barzooka: We did not find any issues relating to the usage of bar graphs.
Results from JetFighter: We did not find any issues relating to colormaps.
Results from rtransparent:- Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
- Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
- No protocol registration statement was detected.
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