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It affects several vital organs, seemingly through a pathological effect on endothelial cells. The SARS-CoV-2 genome encodes 29 proteins, whose contribution to the disease manifestations, and especially endothelial complications, is unknown. We cloned and expressed 26 of these proteins in human cells and characterized the endothelial response to overexpression of each, individually. Whereas most proteins induced significant changes in endothelial permeability, nsp2, nsp5_c145a (catalytic dead mutant of nsp5), and nsp7 also reduced CD31, and increased von Willebrand factor expression and IL-6, suggesting endothelial dysfunction. Using propagation-based analysis of a protein\u2013protein interaction (PPI) network, we predicted the endothelial proteins affected by the viral proteins that potentially mediate these effects. We further applied our PPI model to identify the role of each SARS-CoV-2 protein in other tissues affected by coronavirus disease (COVID-19). While validating the PPI network model, we found that the tight junction (TJ) proteins cadherin-5, ZO-1, and \u03b2-catenin are affected by nsp2, nsp5_c145a, and nsp7 consistent with the model prediction. Overall, this work identifies the SARS-CoV-2 proteins that might be most detrimental in terms of endothelial dysfunction, thereby shedding light on vascular aspects of COVID-19.<\/jats:p>","DOI":"10.7554\/elife.69314","type":"journal-article","created":{"date-parts":[[2021,10,25]],"date-time":"2021-10-25T10:00:20Z","timestamp":1635156020000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.69314","source":"Crossref","is-referenced-by-count":74,"title":["Effect of SARS-CoV-2 proteins on vascular permeability"],"prefix":"10.7554","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8569-0810","authenticated-orcid":true,"given":"Rossana","family":"Rauti","sequence":"first","affiliation":[{"name":"Department of Biomedical Engineering, Tel Aviv University","place":["Tel Aviv, Israel"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5947-484X","authenticated-orcid":true,"given":"Meishar","family":"Shahoha","sequence":"first","affiliation":[{"name":"School of Neurobiology, Biochemistry and Biophysics, The George S. 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