Endothelial activation and dysfunction in COVID-19: from basic mechanisms to potential therapeutic approaches

Abstract

On 12 March 2020, the outbreak of coronavirus disease 2019 (COVID-19) was declared a pandemic by the World Health Organization. As of 4 August 2020, more than 18 million confirmed infections had been reported globally. Most patients have mild symptoms, but some patients develop respiratory failure which is the leading cause of death among COVID-19 patients. Endothelial cells with high levels of angiotensin-converting enzyme 2 expression are major participants and regulators of inflammatory reactions and coagulation. Accumulating evidence suggests that endothelial activation and dysfunction participate in COVID-19 pathogenesis by altering the integrity of vessel barrier, promoting pro-coagulative state, inducing endothelial inflammation, and even mediating leukocyte infiltration. This review describes the proposed cellular and molecular mechanisms of endothelial activation and dysfunction during COVID-19 emphasizing the principal mediators and therapeutic implications.

Fig. 1

Pathophysiology of endothelial cells. Endothelial cells exist in the inner layer of blood vessels (a) such as arteries (b), veins (c), and capillaries (d), and are normally protected by pericytes that support the vessel structure. Tight junctions link neighboring cells and help maintain tissue integrity, act as barriers to permeability. The regulation of vascular tone, and permeability upon activation are illustrated

Fig. 2

Overview of endothelial activation and dysfunction in the pathogenesis of COVID-19. In the initial stage of severe COVID-19 patients, SARS-CoV-2 infection causes acute lung injury, and then excessive cytokines are released from immune cells, bronchial epithelial cells, and alveolar cells. SARS-CoV-2 infection and various cytokines are predicted to cause endothelial activation and dysfunction by multiple pathways, leading to vascular inflammation and permeability. Then more immune cells enter or migrate into alveoli and enhance lung inflammation. With vascular permeability, erythrocytes enter into alveoli, leading to edema. Moreover, with the release of pro-inflammatory cytokines and inflammatory cells to circulation, vasculitis occurs. The disruption of vascular integrity and EC apoptosis leads to the exposure of the thrombogenic basement membrane and the activation of the clotting cascade. Endothelial cells release relevant cytokines that further augment platelet production. Platelet activation is the primary cause of thrombosis. Inflammation, edema, and microthrombus work together to cause ARDS. The transfer of microthrombi into the blood circulation increases the risk of the formation of deep vein thrombosis, which may further cause pulmonary embolism and stroke

Fig. 3

Proposed mechanisms of endothelial activation and dysfunction during COVID-19 This picture highlights possible mechanisms of endothelial activation and dysfunction during SARS-CoV-2 infection, including loss of vascular integrity, vascular permeability, activation of the coagulation pathway, inflammation, and thrombus formation