The Endothelium and COVID-19: An Increasingly Clear Link Brief Title: Endotheliopathy in COVID-19

Abstract

The endothelium has a fundamental role in the cardiovascular complications of coronavirus disease 2019 (COVID-19). Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) particularly affects endothelial cells. The virus binds to the angiotensin-converting enzyme 2 (ACE-2) receptor (present on type 2 alveolar cells, bronchial epithelial cells, and endothelial cells), and induces a cytokine storm. The cytokines tumor necrosis factor alpha, interleukin-1 beta, and interleukin-6 have particular effects on endothelial cells—leading to endothelial dysfunction, endothelial cell death, changes in tight junctions, and vascular hyperpermeability. Under normal conditions, apoptotic endothelial cells are removed into the bloodstream. During COVID-19, however, endothelial cells are detached more rapidly, and do not regenerate as effectively as usual. The loss of the endothelium on the luminal surface abolishes all of the vascular responses mediated by the endothelium and nitric oxide production in particular, which results in greater contractility. Moreover, circulating endothelial cells infected with SARS-CoV-2 act as vectors for viral dissemination by forming clusters that migrate into the circulation and reach distant organs. The cell clusters and the endothelial dysfunction might contribute to the various thromboembolic pathologies observed in COVID-19 by inducing the formation of intravascular microthrombi, as well as by triggering disseminated intravascular coagulation. Here, we review the contributions of endotheliopathy and endothelial-cell-derived extracellular vesicles to the pathogenesis of COVID-19, and discuss therapeutic strategies that target the endothelium in patients with COVID-19.

Endothelial dysfunction in COVID-19: an overview of evidence, biomarkers, mechanisms and potential therapies

“…According to the American-European Consensus Conference on acute respiratory distress syndrome (ARDS), the ARDS is the most severe form of the acute lung injury [ 17 ] as well as ongoing COVID-19 associated lethality [ 18 ]. Pulmonary capillary endothelium provides a fertile “soil” for viral entry, replication, thereby facilitating viral entry to the circulating blood [ 19 , 20 ]. SARS-CoV-2 infects the ECs and epithelial cells in lung tissues via angiotensin-converting enzyme-2 (ACE2) and alternative receptors [ 21 ] on host cells [ 22 ].…”

“…SARS-CoV-2 infects the ECs and epithelial cells in lung tissues via angiotensin-converting enzyme-2 (ACE2) and alternative receptors [ 21 ] on host cells [ 22 ]. Interestingly, live SARS-CoV-2 virus and sera from COVID-19 patients, but not dead virus or spike protein triggers increased endothelial permeability [ 20 , 23 ]. Endothelial integrity is essential for maintaining the pulmonary capillary-alveolar barrier and lung homoeostasis.…”

“…Under physiological conditions, ECs undergoing apoptotic process are released into circulating blood. However, after SARS-CoV-2 infection, ECs are detached more quickly without efficient regeneration [ 20 ]. EC depletion from the luminal surface reduces NO production and impair endothelium-dependent vasorelaxation [ 20 ].…”

Multiple Cerebral Hemorrhages and White Matter Lesions Developing after Severe hMPV Pneumonia in a Patient with Trisomy 13: A Case Report and Review of the Literature

“…Our present case exhibited intracranial hemorrhage similar to that seen in some 2019 novel coronavirus (COVID-19)associated infections that were accompanied by devastating lung disease. The many risk factors included therapeutic anticoagulation, ECMO, mechanical (including ischemic stroke caused by embolisms) (Six et al 2022). However, ischemic stroke after COVID-19 infection has been proposed to be multifactorial in nature, including the development of a cytokine storm, activation of the innate immune system, embolic events triggered by pre-existing or new-onset arrhythmias, hypoxia-induced ischemia secondary to severe pulmonary disease, thrombotic microangiopathy, and direct infection of the brain endothelium that causes viral-induced vasculitis (Zakeri et al 2021).…”

“…the ARDS, and DIC(Daly et al 2021). COVID-19 infects vascular endothelial cells after binding to vascular angiotensin-converting enzyme 2 (ACE2)(Six et al 2022), triggering DIC and multiple organ failure…”