Endothelial cells and SARS-CoV-2: An intimate relationship

Abstract

Angiotensin-converting enzyme 2 (ACE2) is an important player of the renin-angiotensin-aldosterone system (RAAS) in regulating the conversion of angiotensin II into angiotensin (1-7). While expressed on the surface of human cells, such as lung, heart, kidney, neurons, and endothelial cells (EC), ACE2 is the entry receptor for SARS-CoV-2. Here, we would like to highlight that ACE2 is predominant on the EC membrane. Many of coronavirus disease 2019 (COVID-19) symptoms have been associated with the large recruitment of immune cells, directly affecting EC. Additionally, cytokines, hypoxia, and complement activation can trigger the activation of EC leading to the coagulation cascade. The EC dysfunction plus the inflammation due to SARS-CoV-2 infection may lead to abnormal coagulation, actively participating in thrombo-inflammatory processes resulting in vasculopathy and indicating poor prognosis in patients with COVID-19. Considering the intrinsic relationship between EC and the pathophysiology of SARS-CoV-2, EC-associated therapies such as anticoagulants, fibrinolytic drugs, immunomodulators, and molecular therapies have been proposed. In this review, we will discuss the role of EC in the lung inflammation and edema, in the disseminate coagulation process, ACE2 positive cancer patients, and current and future EC-associated therapies to treat COVID-19.

Keywords: ACE2; Coagulation; Endothelial cells; Inflammation; SARS-CoV-2.

Graphical abstract

Fig. 1

Endothelial cells and pulmonary epithelium in SARS-CoV-2 infection. (A) The binding of SARS-CoV-2 to the ACE2 receptor on EC leads to the activation of the complement system, a set of plasma proteins with opsonization functions in the immune system. The activation of the complement system induces pro-inflammatory cytokines release (e.g.: TNFα, IL-1β, IL-6, IL-8) and the recruitment of phagocytic cells. The release of these cytokines promotes the activation of the endothelium leading to the expression of selectins (E-selectin and P-selectin) and integrins (ICAM and VCAM) and promote the recruitment of neutrophils and monocytes, causing damage to the endothelium through the release of ROS, production of NETs, degradation of the extracellular matrix (ECM) and more pro-inflammatory cytokines release. The lesion in the endothelium induces the activation of the coagulation cascade and platelet activation leading to coagulation and thrombosis and increasing D-dimers formation. (B) The SARS-CoV-2 infection activates NLRP3, a cytosolic receptor in phagocyte cells, leading to the inflammasome, activating caspase 1 and exacerbating the production of IL-1β and TNFα, which in turn, lead to the recruitment of neutrophils, increased production of ROS and NETs, causing endothelial damage, pulmonary edema, and cell death.

Fig. 2

Cancer patient risk to SARS-CoV-2 infection could be influenced by ACE2 levels on endothelial cells? (A) Cancer therapeutics and tumor microenvironment can cause immunosuppression, vascular complications and may modulate ACE2 levels in cancer patients. Cancer cells with modified immunogenicity selected immune cells to release immunosuppressive molecules, such as TGFβ, VEGF, PGE2, IL-10, and iNOS, suppressing the proliferation and the cytotoxic response from T-lymphocytes and leading to an anti-inflammatory phenotype (Regulatory T-cells, T-regs). This immunosuppression environment can also induce the recruitment of tumor-associated macrophages with an anti-inflammatory phenotype (TAM-M2) and immature dendritic cells [159]. The chronic immunosuppression in tumor patients can facilitate the infection by SARS-CoV-2 and the COVID-19 severity. (B) Several human disorders can be influenced by levels of ACE2. However, very few are known about ACE2 levels on EC in cancer patients, and this possible increased risk of severity of COVID-19

Fig. 3

Inflammatory environment triggered by SARS-CoV-2 infection and EC-associated therapeutic models. (A) The binding of heparin to antithrombin 3 (ATIII) increases ATIII activity. This leads to exposure of the ATIII catalytic site, which will interact with thrombin and inhibit its activity. This process leads to the inhibition of important factors for the coagulation process, such as IIa, IXa, Xa, XIa, XIIa. (B) Glucocorticoids such as dexamethasone have an important anti-inflammatory action by modulating inflammatory cytokines and COX-2 and PLA2 activity. Cells from the immune system increase the expression of anti-inflammatory molecules and decrease pro-inflammatory expression. Activation of the glucocorticoid receptor blocks the NFκB gene expression and impairs the expression of proinflammatory cytokines such as IL-1, IL-6, IL-8, and TNF-a. Dexamethasone can bind to Annexin I, which inhibits PLA2 activity impairing the conversion of phospholipids in arachidonic acid, which decreases the production of prostaglandins. (C) Tocilizumab is a monoclonal anti-IL-6 (IL-6) antibody which reduces the proinflammatory activity of this cytokine. (D) Type I IFNs are a large family of cytokines that mediate innate antiviral immune responses. Type I IFNs activate the transcription of several genes giving cells resistance to viral infection (antiviral status). Besides, they promote an increase in the lymphocyte population and its toxicity. (E) Soluble recombinant human ACE2 (hrsACE2) may impair the entry of SARS CoV-2 to the host cell.