SARS-CoV-2 infection drives endothelial dysfunction indirectly through hypoxia and increased pro-inflammatory cytokine production

Abstract In the Covid-19 patients, vascular thrombosis is observed in the heart, lung, and other organs, leading to multiorgan morbidity and mortality. We obtained heart and lung tissues from autopsies of the patients who died from Covid-19 or unrelated causes as a control. We found that endothelial cells of the hearts and lungs were in dysfunctional state during Covid-19. Cardiac and pulmonary endothelial cells in the Covid-19 group showed decreased level of thrombomodulin, an anticoagulant, and increased level of von Willebrand factor, a procoagulant, compared to non-Covid-19 control. Endothelial cells in the Covid-19 autopsy hearts and lungs also exhibited reduced ICAM-1, VCAM-1, and E-selectin expression. Most of the hearts from the Covid-19 autopsies tested negative for SARS-CoV-2 genome, while all the lungs tested positive. Human coronary artery endothelial cell (HCAEC) in vitro culture was not infected by SARS-CoV-2, showing no dysfunctional phenotype. In the HCAEC culture and in vivo mouse experiments, hypoxia and pro-inflammatory cytokine treatment caused endothelial cell dysfunction including thrombomodulin downregulation similar to what we observed in Covid-19 autopsy tissues. Collectively, endothelial cell dysfunction associated with thrombus formation in Covid-19 is not caused by direct infection with SARS-CoV-2, but it can be induced by pathogenic microenvironments such as hypoxia and increased pro-inflammatory cytokine milieu.