AUTHOR=Hatch Christopher J. , Piombo Sebastian D. , Fang Jennifer S. , Gach Johannes S. , Ewald Makena L. , Van Trigt William K. , Coon Brian G. , Tong Jay M. , Forthal Donald N. , Hughes Christopher C. W. 

TITLE=SARS-CoV-2 infection of endothelial cells, dependent on flow-induced ACE2 expression, drives hypercytokinemia in a vascularized microphysiological system

JOURNAL=Frontiers in Cardiovascular Medicine

VOLUME=Volume 11 - 2024

YEAR=2024

URL=https://www.frontiersin.org/journals/cardiovascular-medicine/articles/10.3389/fcvm.2024.1360364

DOI=10.3389/fcvm.2024.1360364

ISSN=2297-055X

ABSTRACT=Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes coronavirus disease 2019 (COVID-19) has, to date, resulted in nearly 7 million deaths globally. Severe COVID-19 is associated with a hyperaggressive inflammatory response characterized by hypercytokinemia (i.e., "cytokine storm") and endothelial damage. The development of a vaccine for SARS-CoV-2 has reduced hospitalization rates, but hypercytokinemia remains a major concern among those with breakthrough infections leading to severe COVID-19. This suggests that disease models that recapitulate the COVID-19 hypercytokinemia response are still necessary. Our lab has previously developed a vascularized micro-organ (VMO) microphysiological system that supports de novo formation of a perfused and physiological microvasculature. Here, we adapt the VMO to model endothelial dysfunction following SARS-CoV-2 infection. We find that expression of reninangiotensin signaling axis components, which mediate SARS-CoV-2 cell entry, is preserved in endothelial cells in the VMO compared to 2D monolayer. Additionally, we show that SARS-CoV-2 pseudotyped virus has increased infectivity in the VMO compared to monolayer and that exposure of the VMO to SARS-CoV-2 pseudotyped virus reduces ACE2 expression. Finally, exposure of infected vasculature to recombinant Angiotensin leads to increased expression of several proinflammatory markers, including IL-6. In summary, we demonstrate using a vascularized microphysiological system that SARS-CoV-2 can infect vascular endothelial cells under flow conditions and that this may contribute to the hypercytokinemia frequently seen in COVID-19 patients.