Endotheliopathy in Acute COVID-19 and Long COVID

Abstract

The pulmonary endothelium is a highly regulated organ that performs a wide range of functions under physiological and pathological conditions. Since endothelial dysfunction has been demonstrated to play a direct role in sepsis and acute respiratory distress syndrome, its role in COVID-19 has also been extensively investigated. Indeed, apart from the COVID-19-associated coagulopathy biomarkers, new biomarkers were recognised early during the pandemic, including markers of endothelial cell activation or injury. We systematically searched the literature up to 10 March 2023 for studies examining the association between acute and long COVID-19 severity and outcomes and endothelial biomarkers.

Keywords: COVID-19; biomarkers; endotheliopathy; long COVID.

Figure 1

Endotheliopathy in COVID-19. COVID-19 is characterised by extended endothelial dysfunction. The host immune response to SARS-CoV-2 infection includes the excessive activation of immune cells, releasing vast amounts of pro- and anti-inflammatory cytokines, such as IL-1β, IL-6, IL-8, and TNF-α. Endothelial cells are activated and express adhesion molecules, to which immune cells bind, affecting coagulation, endothelial activation/dysfunction, and vascular barrier permeability. Ang-1 maintains vascular integrity, while Ang-2 counteracts the protective effects of Ang-1. Hence, the release of Ang-2 directly reflects vascular barrier breakdown. The endothelium becomes leaky and inflamed, allowing the transmigration of immune cells to the site of injury. A crucial regulator of endothelial cell homeostasis, tissue oedema, and inflammatory processes is the endothelial glycocalyx (EG). Microvascular leakage can result from glycocalyx dysfunction. Prior to their strong adherence and diapedesis at sites of infection and inflammation, active neutrophils adhere to endothelia through E-selectin and P-selectin. Their strong adherence to the endothelium is controlled by VCAM-1 and ICAM-1, and their subsequent transendothelial migration to infection sites occurs via PECAM-1. In response to pro-inflammatory cytokines and pro-angiogenic substances, the vascular endothelium expresses and secretes endocan, which prevents leukocyte migration. The soluble form of uPAR, suPAR, reflects general activation of the immune system. sTREM-1 is released during infection. Presepsin is an emerging biomarker of infection released by the cleavage of CD14. Coagulation and fibrinolysis are also critical host responses to infection by SARS-CoV-2. The anti-thrombotic, anti-inflammatory, and pro-fibrinolytic phenotype of endothelial cells (ECs) changes to an active state of endothelial dysfunction. ECs actively control haemostasis through the production of pro-thrombotic substances (von Willebrand factor, P-selectin), molecules that restrict coagulation (thrombomodulin), and fibrinolytic factors (plasminogen activators). Up-regulation of the plasminogen activator inhibitor-1 (PAI-1), the major inhibitor of fibrinolysis, leads to a shift from pro- to anti-fibrinolytic phenotypes. The protein C anticoagulant system also involves protein S, and the endothelial receptors TM and EPCR. A soluble form of EPCR (sEPCR) exists in conditions marked by enhanced inflammation. The vascular endothelium also maintains the vascular tone by producing vasoconstrictors and vasodilators, including endothelin-1, angiotensin-2, nitric oxide, and prostacyclin. ACE hydrolyses angiotensin I to angiotensin II and the balance between ACE and ACE2 is thought to be the key regulator of angiotensin II levels. Studies have implicated vascular endothelial growth factors (VEGFs), angiopoietins, and ephrins as key players in vascular development. VEGF is a glycoprotein originally isolated as a permeability factor with unique specificity for vascular ECs but is now known for its mitogenic and angiogenic properties. VEGF and its receptors VEGF-R1 and VEGF-R2 regulate angiogenesis and vascular permeability. ACE, Angiotensin converting enzyme; Ang-1, angiopoietin-1; Ang-2, angiopoietin-2; CD14, cluster of differentiation 14; EC, endothelial cell; IL, interleukin; PAI-1, plasminogen activator inhibitor 1; sEPCR, soluble endothelial protein C receptor; sICAM-1, soluble intercellular adhesion molecule 1; sPECAM-1, soluble platelet endothelial cell adhesion molecule 1; sTM, soluble thrombomodulin; sTREM-1, soluble triggering receptor expressed on myeloid cells 1; suPAR, soluble urokinase-type plasminogen activator receptor; sVCAM-1, soluble vascular adhesion molecule 1; TNF-α, tumour necrosis factor alpha; UPA, urokinase-type plasminogen activator; VEGF, vascular endothelial growth factor; VEGF-R, VEGF receptor; vWf, von Willebrand factor. The image is adapted from [4].

Figure 2

Potential therapeutic strategies for COVID-19-associated endotheliopathy and coagulopathy. Exploring host targets as well as anti-inflammatory and anti-coagulant agents as part of the treatment strategy could benefit hospitalised patients and give relief to individuals suffering from long COVID manifestations. The entry of SARS-CoV-2 into the host results in increased vascular permeability and endothelial cell activation or dysfunction causing a generalised inflammatory state. Main characteristics are the high levels of cytokines, vWf, and endothelial cell adhesion molecules, promoting coagulation and leukocyte recruitment. The increase in PAI-1 levels results in hypofibrinolysis. ACE, angiotensin converting enzyme; ADM, adrenomedullin; Ang-1, angiopoietin-1; Ang-2, angiopoietin-2; EC, endothelial cell; eNOS, endothelial nitric oxide synthase; ET-1, endothelin-1; PAI-1, plasminogen activator inhibitor 1; RAAS, Renin–Angiotensin–Aldosterone System; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; sEPCR, soluble endothelial protein C receptor; sICAM-1, soluble intercellular adhesion molecule 1; sPECAM-1, soluble platelet-endothelial cell adhesion molecule 1; sTM, soluble thrombomodulin; suPAR, soluble urokinase-type plasminogen activator receptor; sVCAM-1, soluble vascular adhesion molecule 1; TF, tissue factor; VE- cadherin, vascular endothelial cadherin; vWf, von Willebrand factor.