viruses Review Endothelium Infection and Dysregulation by SARS-CoV-2: Evidence and Caveats in COVID-19 Isabelle Bernard 1 , Daniel Limonta 2,3 , Lara K. Mahal 4 and Tom C. Hobman 1,2,3,5, *   Citation: Bernard, I.; Limonta, D.; Mahal, L.K.; Hobman, T.C. Endothelium Infection and Dysregulation by SARS-CoV-2: Evidence and Caveats in COVID-19. Viruses 2021, 13, 29. https://doi.org/ 10.3390/v13010029 Academic Editor: Deborah H. Fuller Received: 21 November 2020 Accepted: 25 December 2020 Published: 26 December 2020 Publisher’s Note: MDPI stays neu- tral with regard to jurisdictional claims in published maps and institutional affiliations. Copyright: © 2020 by the authors. Li- censee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/ licenses/by/4.0/). 1 Department of Medical Microbiology & Immunology, University of Alberta, Edmonton, AB T6G 2E1, Canada; icbernar@ualberta.ca 2 Department of Cell Biology, University of Alberta, Edmonton, AB T6G 2H7, Canada; dlimonta@ualberta.ca 3 Li Ka Shing Institute of Virology, University of Alberta, Edmonton, AB T6G 2E1, Canada 4 Department of Chemistry, University of Alberta, Edmonton, AB T6G 2G2, Canada; lkmahal@ualberta.ca 5 Women & Children’s Health Research Institute, University of Alberta, Edmonton, AB T6G 1C9, Canada * Correspondence: tom.hobman@ualberta.ca; Tel.: +01-780-492-6485 Abstract: The ongoing pandemic of coronavirus disease 2019 (COVID-19) caused by the acute res- piratory syndrome-coronavirus-2 (SARS-CoV-2) poses a persistent threat to global public health. Although primarily a respiratory illness, extrapulmonary manifestations of COVID-19 include gas- trointestinal, cardiovascular, renal and neurological diseases. Recent studies suggest that dysfunction of the endothelium during COVID-19 may exacerbate these deleterious events by inciting inflam- matory and microvascular thrombotic processes. Although controversial, there is evidence that SARS-CoV-2 may infect endothelial cells by binding to the angiotensin-converting enzyme 2 (ACE2) cellular receptor using the viral Spike protein. In this review, we explore current insights into the rela- tionship between SARS-CoV-2 infection, endothelial dysfunction due to ACE2 downregulation, and deleterious pulmonary and extra-pulmonary immunothrombotic complications in severe COVID-19. We also discuss preclinical and clinical development of therapeutic agents targeting SARS-CoV-2- mediated endothelial dysfunction. Finally, we present evidence of SARS-CoV-2 replication in primary human lung and cardiac microvascular endothelial cells. Accordingly, in striving to understand the parameters that lead to severe disease in COVID-19 patients, it is important to consider how direct infection of endothelial cells by SARS-CoV-2 may contribute to this process. Keywords: COVID-19; SARS-CoV-2; ACE2; RAAS; bradykinin–kallikrein pathway; ADAM17; en- dothelial dysfunction; pericyte; immunothrombosis; therapeutics 1. Introduction Coronavirus disease-2019 (COVID-19) is primarily a respiratory illness caused by the severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2). In December 2019, pneumonia cases of unknown etiology were reported in Wuhan, the capital city of Hubei province in China [1,2], after which the new coronavirus spread globally and was conse- quently deemed a pandemic by the World Health Organization in March 2020 [3]. COVID-19 symptoms most commonly reported include fever, cough, and shortness of breath or difficulty breathing [4,5]. In more severe cases, the disease can progress to acute respiratory distress syndrome (ARDS) and hypoxic respiratory failure, which is the leading cause of mortality in COVID-19 patients [4–6]. Although pulmonary manifestations are the major presentations of COVID-19, other important extrapulmonary events include gastrointestinal complications [7,8], cardiovascular injury [7,9], renal dysfunction [7,10,11], and neurological disorders [7,12,13]. Multiple studies have found that microvascular thrombotic and inflammatory processes may play a role in exacerbating ARDS and extra- pulmonary events in COVID-19 patients [10,14–16]. These deleterious complications likely result from dysfunction of the vascular endothelium [10,15–17]. Viruses 2021, 13, 29. https://doi.org/10.3390/v13010029 https://www.mdpi.com/journal/viruses