Endothelial cell activation, Weibel-Palade body secretion, and enhanced angiogenesis in severe COVID-19
Ellie Karampini, Helen Fogarty, Stephanie Elliott, Hannah Morrin, Colm Bergin, Jamie M. O’Sullivan, Mary Byrne, Ignacio Martín‐Loeches, Patrick Mallon, Gerard F. Curley, Siobhán Glavey, Ross Baker, Michelle Lavin, Roger J. S. Preston, Clíona Ní Cheallaigh, Soracha E. Ward, James S. O’Donnell
Abstract
Background Severe COVID-19 is associated with marked endothelial cell (EC) activation that plays a key role in immunothrombosis and pulmonary microvascular occlusion. However, the biological mechanisms through which SARS-CoV-2 causes EC activation and damage remain poorly defined. Objectives We investigated EC activation in patients with acute COVID-19, and specifically focused on how proteins stored within Weibel-Palade bodies may impact key aspects of disease pathogenesis. Methods Thirty-nine patients with confirmed COVID-19 were recruited. Weibel-Palade body biomarkers (von Willebrand factor [VWF], angiopoietin-2 [Angpt-2], and osteoprotegerin) and soluble thrombomodulin (sTM) levels were determined. In addition, EC activation and angiogenesis were assessed in the presence or absence of COVID-19 plasma incubation. Results Markedly elevated plasma VWF antigen, Angpt-2, osteoprotegerin, and sTM levels were observed in patients with acute COVID-19. The increased levels of both sTM and Weibel-Palade body components (VWF, osteoprotegerin, and Angpt-2) correlated with COVID-19 severity. Incubation of COVID-19 plasma with ECs triggered enhanced VWF secretion and increased Angpt-2 expression, as well as significantly enhanced in vitro EC tube formation and angiogenesis. Conclusion We propose that acute SARS-CoV-2 infection leads to a complex and multifactorial EC activation, progressive loss of thrombomodulin, and increased Angpt-2 expression, which collectively serve to promote a local proangiogenic state.