Endothelium Infection and Dysregulation by SARS-CoV-2: Evidence and Caveats in COVID-19

Abstract

The ongoing pandemic of coronavirus disease 2019 (COVID-19) caused by the acute respiratory 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 gastrointestinal, cardiovascular, renal and neurological diseases. Recent studies suggest that dysfunction of the endothelium during COVID-19 may exacerbate these deleterious events by inciting inflammatory 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 relationship 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.

Long-Lasting Cognitive Abnormalities after COVID-19

“…The pathophysiology that underlies cerebrovascular events in patients with COVID-19 is still poorly understood but is likely to be multifactorial. Infection of vascular endothelial cells (which express ACE2 receptors), potential changes of vascular smooth muscle cells (VSMC) in the arteriole, hypercoagulability, and abnormal immune responses can all concur in damaging the vascular system and may increase the risk of cerebrovascular events [16][17][18][19][20][21][22]. Finally, recent evidence indicates that patients who have recovered from COVID-19 might be at increased risk of cognitive decline [23].…”

Endothelial Dysfunction and SARS-CoV-2 Infection: Association and Therapeutic Strategies

“…ECs can mediate the activation of Ag specific memory or effector CD4 and CD8 T lymphocytes, but cannot activate naïve lymphocytes [ 3 ]. It has been reported that vascular ECs could promote the clearance of cells infected by virus via presenting viral peptides to CD8+T cells [ 12 , 43 ]. Microvascular ECs have been reported to induce the trans-endothelial migration of memory or effector CD4 T lymphocytes [ 17 , 44 ].…”

“…IL-6 induces ECs to secrete pro-inflammatory/chemokines and activate C5a complement [ 3 , 50 , 51 ]. Evidence of elevated levels of C5a can be found in a number of clinical studies, including one that confirmed elevated levels of C5a in 39 patients with COVID-19 undergoing maintenance hemodialysis [ 12 , 52 ]. C5a mediates the activation and recruitment of leukocytes by binding to the receptor of C5a, thus promoting the degradation of vascular endothelial (VE)-cadherin and further leading to the destruction of the endothelial barrier [ 17 , 53 , 54 ].…”

“…C5a mediates the activation and recruitment of leukocytes by binding to the receptor of C5a, thus promoting the degradation of vascular endothelial (VE)-cadherin and further leading to the destruction of the endothelial barrier [ 17 , 53 , 54 ]. Treatment of COVID-19 patients with anti-C5a antibodies has been shown to reduce systemic inflammation and increase lung oxygenation [ 12 , 55 ]. To date, the role of C5a in the pathophysiological process of COVID-19 remains unclear.…”

“…Both clinical studies and autopsy findings have shown evidence of vascular damage and thrombotic complications in multiple organs, such as acute ischemic or hemorrhagic stroke, myocardial injury, liver injury, acute kidney injury, as well as intestinal damage [ 6 , 7 , 8 , 9 , 10 , 11 ]. A number of studies have found that inflammatory processes, coagulation disorders, and microvascular thrombosis may exacerbate adult respiratory syndrome (ARDS) and extrapulmonary events in COVID-19 [ 12 , 13 ]. In addition, evidence suggests that the symptoms and signs of patients severely infected with COVID-19 are similar to the clinical phenotypes of endothelial dysfunction and have the same pathophysiological mechanism [ 6 , 14 ].…”