Vascular dysregulation following SARS-CoV-2 infection involves integrin signalling through a VE-Cadherin mediated pathway
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Abstract
The vascular barrier is heavily injured following SARS-CoV-2 infection and contributes enormously to life-threatening complications in COVID-19. This endothelial dysfunction is associated with the phlogistic phenomenon of cytokine storms, thrombotic complications, abnormal coagulation, hypoxemia, and multiple organ failure. The mechanisms surrounding COVID-19 associated endotheliitis have been widely attributed to ACE2-mediated pathways. However, integrins have emerged as possible receptor candidates for SARS-CoV-2, and their complex intracellular signalling events are essential for maintaining endothelial homeostasis. Here, we showed that the spike protein of SARS-CoV-2 depends on its RGD motif to drive barrier dysregulation through hijacking integrin αVβ3. This triggers the redistribution and internalization of major junction protein VE-Cadherin which leads to the barrier disruption phenotype. Both extracellular and intracellular inhibitors of integrin αVβ3 prevented these effects, similarly to the RGD-cyclic peptide compound Cilengitide, which suggests that the spike protein – through its RGD motif – binds to αVβ3 and elicits vascular leakage events. These findings support integrins as an additional receptor for SARS-CoV-2, particularly as integrin engagement can elucidate many of the adverse endothelial dysfunction events that stem from COVID-19.
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SciScore for 10.1101/2022.03.15.484274: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Ethics not detected. Sex as a biological variable not detected. Randomization not detected. Blinding not detected. Power Analysis not detected. Table 2: Resources
Antibodies Sentences Resources After incubation for 1 hour with AlexaFluor 405-labeled spike protein antibodies (FAB105403V, 1:100), absorbance was measured at 405 nm. spike protein antibodies (FAB105403Vsuggested: NoneCells grown on glass slides were infected and stained using anti-VE-Cadherin mouse monoclonal IgG1 antibody, conjugated to AlexaFluor 488 (F-8 sc-9989, 1:100), overlaid onto Fluoroshield mounting medium (ab104139). anti-VE-Cadherinsuggested: (Santa Cruz Biotechnology Cat# sc-9989, RRID:AB_2077957)IgG1suggested: (Santa Cruz Biotechnology …SciScore for 10.1101/2022.03.15.484274: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Ethics not detected. Sex as a biological variable not detected. Randomization not detected. Blinding not detected. Power Analysis not detected. Table 2: Resources
Antibodies Sentences Resources After incubation for 1 hour with AlexaFluor 405-labeled spike protein antibodies (FAB105403V, 1:100), absorbance was measured at 405 nm. spike protein antibodies (FAB105403Vsuggested: NoneCells grown on glass slides were infected and stained using anti-VE-Cadherin mouse monoclonal IgG1 antibody, conjugated to AlexaFluor 488 (F-8 sc-9989, 1:100), overlaid onto Fluoroshield mounting medium (ab104139). anti-VE-Cadherinsuggested: (Santa Cruz Biotechnology Cat# sc-9989, RRID:AB_2077957)IgG1suggested: (Santa Cruz Biotechnology Cat# sc-9989, RRID:AB_2077957)Fluoroshield mounting mediumsuggested: NoneProteins (10 μg) were loaded into an SDS-PAGE and stained using anti-VE-Cadherin mouse antibodies (F-8, sc-9989, 1:200) followed by anti-mouse secondary antibodies (sc-525405, 1:5000). anti-mousesuggested: NoneResults 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: No clinical trial numbers were referenced.
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.
- No funding statement was detected.
- No protocol registration statement was detected.
Results from scite Reference Check: We found no unreliable references.
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