PMC:7386875 / 18198-22929 JSONTXT

{"target":"https://pubannotation.org/docs/sourcedb/PMC/sourceid/7386875","sourcedb":"PMC","sourceid":"7386875","source_url":"https://www.ncbi.nlm.nih.gov/pmc/7386875","text":"COVID-19 and the Endothelium—Hijacking the Guardian of Vascular Integrity\nThe primary site of human infection with SARS-CoV-2 is the lung, where S1 attaches with high affinity to ACE-2 expressed on lung alveolar type II epithelial cells (Figure 1).1,2,5 The replication and release of virus from infected cells results in pyroptosis, a highly inflammatory form of cell death that is a common feature among many cytopathic viruses. PRR (Pattern recognition receptors), such as TLR (Toll-like receptors), subsequently detect the release of pathogen-associated molecular patterns, and intracellular danger-associated molecular patterns, such as ATP and DNA, which evokes an intense inflammatory reaction and triggers the release of proinflammatory chemokines and cytokines from neighboring cells (Figure 1).46 Strikingly, SARS-CoV-2 has been found to contain multiple single-stranded RNA fragments that can be recognized by TLR-7 and TLR-8, similar in numbers to MERS-CoV but more than SARS-CoV.47 The recognition of SARS-CoV-2 by these receptors may contribute to innate immune hyperactivation and the cytokine storm often seen in severe COVID-19.\nIn the setting of SARS-CoV-2 infection, the vascular endothelium appears to be targeted directly by the virus as well as the milieu of proinflammatory cytokines elicited by the immune response.48 ACE-2 is also expressed widely in extrapulmonary sites including blood vessels, heart, kidney, and intestine.49,50 Accordingly, viral RNA has been detected in urine and stool samples from patients with COVID-19.51,52 In this regard, it is currently hypothesized that viral entry via endothelial-expressed ACE-2 represents a mechanism by which the virus can enter and infect other tissues. Recent experimental data have highlighted the ability of COVID-19 to infect human endothelial cells. Indeed, human blood vessel organoids, which closely resemble human capillaries, contain viral RNA after exposure to COVID-19 in vitro.53 Strikingly, the application of human recombinant soluble ACE-2 markedly inhibited viral infection in human capillary organoids, pointing to a direct role for endothelial ACE-2 in viral uptake in blood vessels. Intriguingly, the uptake of SARS-CoV-2 into cells is associated with the downregulation of ACE-2 expression.54,55 This appears to play an important role in promoting a proinflammatory and prothrombotic milieu since ACE-2 plays a pivotal role in regulating the RAS (renin-angiotensin system), by degrading angiotensin II to angiotensin 1–7. While angiotensin II induces vasoconstriction and promotes a proinflammatory/prothrombotic phenotype, angiotensin 1–7 opposes these effects via binding to the MAS receptor, which is widely expressed including on endothelial cells and platelets.55\nInterestingly, patients with SARS-CoV-2 have been demonstrated to have increased levels of IL (interleukin)-6, IL-1β, IFN (interferon)-γ, MCP-1 (monocyte chemoattractant protein 1), MIP (macrophage inflammatory protein), and IP10 (CXCL10).11 These proinflammatory cytokines can disrupt endothelial function and integrity leading to the release of VWF, upregulation of adhesion molecules, such as ICAM (intercellular adhesion molecule)-1, integrin αvβ3, P- and E-selectin, and the production of endothelial cytokines and chemokines.56,57 Thus, the endothelium adopts a proinflammatory and procoagulant phenotype that supports the recruitment of platelets and leukocytes.58,59 Furthermore, these changes are associated with the downregulation of the natural anticoagulants and corresponding upregulation of endothelial tissue factor (TF, CD142).57 Moreover, a common finding in patients with COVID-19 is profound hypoxia. Although not formally tested in the context of SARS-CoV-2 infection, hypoxia is also likely to induce a prothrombotic endothelial phenotype since vascular hypoxia induces the activation of HIFs (hypoxia-inducible transcription factors) that have been demonstrated to upregulate endothelial TF expression while downregulating the natural anticoagulants, Protein S and TFPI (tissue factor pathway inhibitor), thus imparting a procoagulant endothelial phenotype.60\nA recent case series of autopsy sections from patients with COVID-19 aligns with these experimental findings described above and highlight the ability of COVID-19 to infect endothelial cells and cause endothelial injury. Sections of lung, kidney, and intestine from patients with COVID-19 demonstrate evidence of viral inclusion within endothelial cells, in addition to histological evidence of endothelial inflammation and cell death.48 These data point to a direct role of COVID-19 in promoting systemic microvascular dysfunction which potentially promotes a prothrombotic 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