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However, emerging evidence does not support direct infection of endothelial or other vascular wall cells, and thus inflammation may be better explained as a secondary response to epithelial cell infection. In this study, we sought to determine whether lung endothelial or other resident vascular cells are susceptible to productive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and how local complement activation contributes to endothelial dysfunction and inflammation in response to hypoxia and SARS-CoV-2\u2013infected lung alveolar epithelial cells. We found that ACE2 (angiotensin-converting enzyme 2) and TMPRSS2 (transmembrane serine protease 2) mRNA expression in lung vascular cells, including primary human lung microvascular endothelial cells (HLMVECs), pericytes, smooth muscle cells, and fibroblasts, was 20- to 90-fold lower compared with primary human alveolar epithelial type II cells. Consistently, we found that HLMVECs and other resident vascular cells were not susceptible to productive SARS-CoV-2 infection under either normoxic or hypoxic conditions. However, viral uptake without replication (abortive infection) was observed in HLMVECs when exposed to conditioned medium from SARS-CoV-2\u2013infected human ACE2 stably transfected A549 epithelial cells. Furthermore, we demonstrated that exposure of HLMVECs to conditioned medium from SARS-CoV-2\u2013infected human ACE2 stably transfected A549 epithelial cells and hypoxia resulted in upregulation of inflammatory factors such as ICAM-1 (intercellular adhesion molecule 1), VCAM-1 (vascular cell adhesion molecule 1), and IL-6 (interleukin 6) as well as complement components such as C3 (complement C3), C3AR1 (complement C3a receptor 1), C1QA (complement C1q A chain), and CFB (complement factor B). Taken together, our data support a model in which lung endothelial and vascular dysfunction during COVID-19 involves the activation of complement and inflammatory signaling and does not involve productive viral infection of endothelial cells.<\/jats:p>","DOI":"10.1165\/rcmb.2022-0373oc","type":"journal-article","created":{"date-parts":[[2023,4,18]],"date-time":"2023-04-18T16:20:38Z","timestamp":1681834838000},"page":"210-219","update-policy":"https:\/\/doi.org\/10.1164\/crossmarkpolicies","source":"Crossref","is-referenced-by-count":6,"title":["Local Complement Contributes to Pathogenic Activation of Lung Endothelial Cells in SARS-CoV-2 Infection"],"prefix":"10.1093","volume":"69","author":[{"given":"Hui","family":"Zhang","sequence":"first","affiliation":[{"name":"Cardiovascular Pulmonary Research Laboratories, Department of Pediatrics and Medicine"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Evgenia","family":"Gerasimovskaya","sequence":"additional","affiliation":[{"name":"Cardiovascular Pulmonary Research Laboratories, Department of Pediatrics and Medicine"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mary K.","family":"McCarthy","sequence":"additional","affiliation":[{"name":"Department of Immunology and Microbiology, and"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nicholas A.","family":"May","sequence":"additional","affiliation":[{"name":"Department of Immunology and Microbiology, and"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ram Raj","family":"Prasad","sequence":"additional","affiliation":[{"name":"Cardiovascular Pulmonary Research Laboratories, Department of Pediatrics and Medicine"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Suzette","family":"Riddle","sequence":"additional","affiliation":[{"name":"Cardiovascular Pulmonary Research Laboratories, Department of Pediatrics and Medicine"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"B. 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