Endothelial Dysfunction in COVID-19: Potential Mechanisms and Possible Therapeutic Options

Abstract

SARS-CoV-2, a novel coronavirus found in Wuhan (China) at the end of 2019, is the etiological agent of the current pandemic that is a heterogeneous disease, named coronavirus disease 2019 (COVID-19). SARS-CoV-2 affects primarily the lungs, but it can induce multi-organ involvement such as acute myocardial injury, myocarditis, thromboembolic eventsandrenal failure. Hypertension, chronic kidney disease, diabetes mellitus and obesity increase the risk of severe complications of COVID-19. There is no certain explanation for this systemic COVID-19 involvement, but it could be related to endothelial dysfunction, due to direct (endothelial cells are infected by the virus) and indirect damage (systemic inflammation) factors. Angiotensin-converting enzyme 2 (ACE2), expressed in human endothelium, has a fundamental role in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. In fact, ACE2 is used as a receptor by SARS-CoV-2, leading to the downregulation of these receptors on endothelial cells; once inside, this virus reduces the integrity of endothelial tissue, with exposure of prothrombotic molecules, platelet adhesion, activation of coagulation cascades and, consequently, vascular damage. Systemic microangiopathy and thromboembolism can lead to multi-organ failure with an elevated risk of death. Considering the crucial role of the immunological response and endothelial damage in developing the severe form of COVID-19, in this review, we will attempt to clarify the underlying pathophysiological mechanisms.

Keywords: COVID-19; SARS-CoV-2; coagulopathy; endothelium; inflammation; pathogenesis.

Figure 1

(A) The S protein of the virus attacks the lung and other organs, due to using the ACE2 receptor. The S protein is composed of two subunits: S1 of the RBD that binds ACE2 and S2 that anchors the virion to the membrane leading the fusion. Subunit S2 is activated thanks to the TMPRSS-2and ADAM17 of the host. In the lung, through the ACE/Ang II axis/AT1 system, ACE converts Ang I into Ang II, which leads to the release of aldosterone leading to a vasopressor effect, with increased peripheral vascular resistance and retention of water and sodium due to release of aldosterone. (B) The action of ACE2, on the other hand, generates several molecules (Ang (1–9), Ang (1–5) and Ang (1–7)); Ang (1–7) constitutes the final molecule in this series and acts on the Mas receptor, promoting vasodilation and antioxidant and antiproliferative effects. SARS-CoV-2 competes with Ang II for ACE2 and this leads to its downregulation, determining an imbalance of ACE/ACE2, and it hyperactivates the ACE/Ang II/AT1R axis, resulting in a decrease inAng (1–7) [12,13,14,15,16,17,18,19,20].

Figure 2

SARS-CoV-2 determines both an increase in ROS and the imbalance of ACE/ACE2. The former mechanism results in recruitment of M1 macrophages and neutrophils, where as the latter, due to the prevalence of ACE, further stimulates ROS production and inflammation. Moreover, it lessens NO synthesis in addition to having a vasoconstriction effect. All these mechanisms induce damage to the endothelium and increase the permeability of vessels, the consumption of NO and lipid membrane peroxidation. Endothelial injury causes increased expression of thromboxane and adhesion receptors, such as those for VWF, recruiting platelets, leucocytes and all inflammatory cells, inducing thrombus formation. This hypercoagulability compromises perfusion of organs, such as the lung, myocardium and kidney, to the point of manifestation of DIC. Furthermore, COVID-19 inflammation activates factor Xa, which stimulates inflammation (through IL-6 induction) and angiogenesis [2,22,26,29,31,32,34,36,37,48,49].