{"doi":"10.3389/fcimb.2021.701278","title":"SARS-CoV-2 Infects Endothelial Cells In Vivo and In Vitro","abstract":"SARS-CoV-2 infection can cause fatal inflammatory lung pathology, including thrombosis and increased pulmonary vascular permeability leading to edema and hemorrhage. In addition to the lung, cytokine storm-induced inflammatory cascade also affects other organs. SARS-CoV-2 infection-related vascular inflammation is characterized by endotheliopathy in the lung and other organs. Whether SARS-CoV-2 causes endotheliopathy by directly infecting endothelial cells is not known and is the focus of the present study. We observed 1) the co-localization of SARS-CoV-2 with the endothelial cell marker CD31 in the lungs of SARS-CoV-2-infected mice expressing hACE2 in the lung by intranasal delivery of adenovirus 5-hACE2 (Ad5-hACE2 mice) and non-human primates at both the protein and RNA levels, and 2) SARS-CoV-2 proteins in endothelial cells by immunogold labeling and electron microscopic analysis. We also detected the co-localization of SARS-CoV-2 with CD31 in autopsied lung tissue obtained from patients who died from severe COVID-19. Comparative analysis of RNA sequencing data of the lungs of infected Ad5-hACE2 and Ad5-empty (control) mice revealed upregulated KRAS signaling pathway, a well-known pathway for cellular activation and dysfunction. Further, we showed that SARS-CoV-2 directly infects mature mouse aortic endothelial cells (AoECs) that were activated by performing an aortic sprouting assay prior to exposure to SARS-CoV-2. This was demonstrated by co-localization of SARS-CoV-2 and CD34 by immunostaining and detection of viral particles in electron microscopic studies. Moreover, the activated AoECs became positive for ACE-2 but not quiescent AoECs. Together, our results indicate that in addition to pneumocytes, SARS-CoV-2 also directly infects mature vascular endothelial cells in vivo and ex vivo , which may contribute to cardiovascular complications in SARS-CoV-2 infection, including multipleorgan failure.","journal":"Frontiers in Cellular and Infection Microbiology","year":2021,"id":147695,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":149,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9547,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":322666,"name":"Kun Han","orcid":"0000-0002-4327-3901","position":1,"is_corresponding":false},{"id":259605,"name":"Robert V. Blair","orcid":"0000-0001-9616-9414","position":2,"is_corresponding":false},{"id":628334,"name":"Kornelia Kenst","orcid":"0000-0003-3035-9615","position":3,"is_corresponding":false},{"id":276181,"name":"Zhongnan Qin","orcid":null,"position":4,"is_corresponding":false},{"id":628335,"name":"Berin Upcin","orcid":"0000-0003-4853-9358","position":5,"is_corresponding":false},{"id":628336,"name":"Philipp Wörsdörfer","orcid":"0000-0003-3398-3229","position":6,"is_corresponding":false},{"id":259611,"name":"Cecily C. Midkiff","orcid":"0000-0001-9322-8730","position":7,"is_corresponding":false},{"id":293286,"name":"Joseph C. Mudd","orcid":null,"position":8,"is_corresponding":false},{"id":629423,"name":"Elizaveta Belyaeva","orcid":null,"position":9,"is_corresponding":false},{"id":629424,"name":"Nicholas S. Milligan","orcid":null,"position":10,"is_corresponding":false},{"id":629425,"name":"Tyler D. Rorison","orcid":null,"position":11,"is_corresponding":false},{"id":628337,"name":"Nicole Wagner","orcid":"0000-0002-1049-4062","position":12,"is_corresponding":false},{"id":628338,"name":"Jochen Bodem","orcid":"0000-0003-1908-4091","position":13,"is_corresponding":false},{"id":32238,"name":"Lars Dölken","orcid":"0000-0002-4651-3544","position":14,"is_corresponding":false},{"id":273763,"name":"Bertal H. Aktas","orcid":"0000-0001-7829-4553","position":15,"is_corresponding":false},{"id":251271,"name":"Richard S. Vander Heide","orcid":"0000-0002-3809-2698","position":16,"is_corresponding":false},{"id":232364,"name":"Xiao‐Ming Yin","orcid":"0000-0002-8576-6093","position":17,"is_corresponding":false},{"id":246970,"name":"Jay K. Kolls","orcid":"0000-0001-5151-6304","position":18,"is_corresponding":false},{"id":218444,"name":"Chad J. Roy","orcid":"0000-0002-1710-6974","position":19,"is_corresponding":false},{"id":237299,"name":"Jay Rappaport","orcid":"0000-0001-7916-3571","position":20,"is_corresponding":false},{"id":373586,"name":"Süleyman Ergün","orcid":"0000-0002-2112-5377","position":21,"is_corresponding":false},{"id":237300,"name":"Xuebin Qin","orcid":"0000-0001-9875-983X","position":22,"is_corresponding":false},{"id":237297,"name":"Fengming Liu","orcid":"0000-0002-8815-3356","position":0,"is_corresponding":true}],"reference_count":55,"raw_metadata":null,"created_at":"2026-07-18T23:42:35.448762Z","pmid":"34307198","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}