Endothelial dysfunction in COVID-19: an overview of evidence, biomarkers, mechanisms and potential therapies

• Published in: Acta pharmacologica Sinica Vol. 44; no. 4; pp. 695 - 709
• Main Authors: Xu, Suo-wen, Ilyas, Iqra, Weng, Jian-ping
• Format: Journal Article
• Language: English
• Published: Singapore Springer Nature Singapore 01-04-2023; Nature Publishing Group
• Subjects: Animal models; Animals; Bioavailability; Biomarkers; Biomedical and Life Sciences; Biomedicine; Cell activation; Coronaviruses; COVID-19; COVID-19 - pathology; Cytokine storm; Drug delivery; Drug development; Drug discovery; Endothelial cells; Endothelial Cells - pathology; Humans; Immunology; Infections; Internal Medicine; Medical Microbiology; Nitric oxide; Oxidative stress; Pharmacology/Toxicology; Post-Acute COVID-19 Syndrome; Review; Review Article; SARS-CoV-2; Senescence; Severe acute respiratory syndrome coronavirus 2; Thrombosis; Vaccine; Vasoactive agents; COVID-19; SARS-CoV-2; endothelialitis; endotheliitis; endothelial dysfunction
• ISSN: 1671-4083; 1745-7254
• DOI: 10.1038/s41401-022-00998-0

The fight against coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 infection is still raging. However, the pathophysiology of acute and post-acute manifestations of COVID-19 (long COVID-19) is understudied. Endothelial cells are sentinels lining the innermost layer of blood vessel that gatekeep micro- and macro-vascular health by sensing pathogen/danger signals and secreting vasoactive molecules. SARS-CoV-2 infection primarily affects the pulmonary system, but accumulating evidence suggests that it also affects the pan-vasculature in the extrapulmonary systems by directly (via virus infection) or indirectly (via cytokine storm), causing endothelial dysfunction (endotheliitis, endothelialitis and endotheliopathy) and multi-organ injury. Mounting evidence suggests that SARS-CoV-2 infection leads to multiple instances of endothelial dysfunction, including reduced nitric oxide (NO) bioavailability, oxidative stress, endothelial injury, glycocalyx/barrier disruption, hyperpermeability, inflammation/leukocyte adhesion, senescence, endothelial-to-mesenchymal transition (EndoMT), hypercoagulability, thrombosis and many others. Thus, COVID-19 is deemed as a (micro)vascular and endothelial disease. Of translational relevance, several candidate drugs which are endothelial protective have been shown to improve clinical manifestations of COVID-19 patients. The purpose of this review is to provide a latest summary of biomarkers associated with endothelial cell activation in COVID-19 and offer mechanistic insights into the molecular basis of endothelial activation/dysfunction in macro- and micro-vasculature of COVID-19 patients. We envisage further development of cellular models and suitable animal models mimicking endothelial dysfunction aspect of COVID-19 being able to accelerate the discovery of new drugs targeting endothelial dysfunction in pan-vasculature from COVID-19 patients.