Endothelial Permeability and the Angiopoietin/Tie2 System Following Mild and Severe COVID-19
Authors: Volleman Carolien , Ibelings Roselique , Vlaar Alexander P. J. , van den Brom Charissa E. ,   The Amsterdam UMC COVID-19 Biobank Study Group, van Agtmael M. A. , Algera A. G. , van Amstel R , Appelman B , van Baarle F. E. H. P. , Bax D. J. C. , Beudel M , Boogaard H. J. , Bomers M , Bonta P. I. , Bos L. D. J. , Botta M , de Brabander J , de Bree G. J. , de Bruin S , Bugiani M , Buis D , Bulle E. B. , Chouchane O , Cloherty A. P. M. , de Rotte M. C. F. J. , Dijkstra M , Dongelmans D. A. , Dujardin R. W. G. , Elbers P. E. , Fleuren L. M. , Geerlings S. E. , Geijtenbeek T. B. H. , Girbes A. R. J. , Goorhuis A , Grobusch M. P. , Hafkamp F. M. J. , Hagens L. A. , Hamann J , Harris V. C. , Hemke R , Hermans S. M. , Heunks L. M. A. , Hollmann M. W. , Horn J , Hovius J. W. , de Jong M. D. , Koning R , Lim E. H. T. , van Mourik N , Nellen J. F. , Nossent E. J. , Paulus F , Peters E , Piña-Fuentes D , vander Poll T , Preckel B , Prins J. M. , Raasveld S. J. , Reijnders T. D. Y. , Schinkel M , Schrauwen F. A. P. , Schultz M. J. , Schuurman A. R. , Schuurmans J , Sigaloff K , Slim M. A. , Smeele P , Smit M. R. , Stijnis C , Stilma W , Teunissen C. E. , Thoral P , Tsonas A. M. , Tuinman P. R. , vander Valk M , Veelo D. P. , Volleman C , Vries H , van Vught L. A. , van Vugt M , Wouters D , Zwinderman A. H. , Brouwer M. C. , Wiersinga W. J. , Vlaar A. P. J. , van Beek D 
Published: July 2023

Endotheliopathy plays a role in the development of acute kidney and lung injury in COVID-19, probably due to inflammation, endothelial permeability, vascular leakage and edema formation. This study examined alterations in the circulation of patients with mild and severe COVID-19 on in vitro endothelial permeability and its relation to the endothelial angiopoietin/Tie2 system, which is involved in the regulation of endothelial permeability. Plasma was obtained from COVID-19 patients admitted to the ward (n = 14) or ICU (n = 20) at admission and after 1 and 2 weeks and healthy controls (n = 5). Human kidney and lung endothelial cells were exposed to patient plasma and treated with recombinant angiopoietin-1. In vitro endothelial barrier function was assessed using electric cell-substrate impedance sensing. Circulating markers of the angiopoietin/Tie2 system, endothelial dysfunction and glycocalyx degradation were measured by ELISA. Plasma from COVID-19 patients reduced endothelial resistance compared to healthy controls, but COVID-19 plasma-induced drop in endothelial resistance did not differ between ward and ICU patients. Circulating angiopoietin-2, soluble Tie2 and soluble Tie1 levels increased over time in ICU patients, whereas levels remained stable in ward patients. The increase in angiopoietin-2 was able to predict 90-day mortality (AUC = 0.914, p < 0.001). Treatment with recombinant angiopoietin-1 did not restore COVID-19 plasma-induced hyperpermeability. In conclusion, these results suggest that indirect effects of the virus represented in the circulation of COVID-19 patients induced endothelial hyperpermeability irrespective of disease severity and changes in the endothelial angiopoietin/Tie2 system. Nonetheless, angiopoietin-2 might be of interest in the context of organ injury and patient outcome in COVID-19.