Abstract 111: Vein-Chip Is A New Experimental Model To Predict Pathophysiology Of SARS-CoV-2 Induced Thrombosis
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There is a serious limitation of experimental models that can improve our limited knowledge of the mechanisms that regulate endotheliopathy and venous thrombosis (VT) clinically observed frequently amongst the most severe COVID-19 patients. Also, while observation and study of VT in humans are difficult due to the deep-lying nature of the deep veins in which VT develops, lab animal models do not include the venous valves, which are the sites for thrombus development in humans. We develop a Vein-chip microfluidic platform that includes venous valve architecture, endothelial cells (ECs), and whole blood flow, which can include the three factors of Virchows triad - endothelial inflammation, stasis of blood flow, and coagulable nature of blood. Our in silico and in vitro observations with Vein-Chip reveal that incompetent valves and thrombosis changes the blood flow pattern in and around the venous valves. We show that healthy endothelium at the venous valve cusps adapt to the complex flow patterns and have an anti-thrombotic phenotype compared to the venous lumen. But exposure of the lumen to living and replicating SARS-CoV-2 virus and inflammatory cytokines found in COVID-19 patient samples inflames the lumen and the valve endothelium becomes pro-thrombotic. Interestingly, when we directed our investigation to analyze the ACE2 expression on these cells, as ACE2 is the functional receptor of the SARS-CoV-2 virus, we found that ACE2 expression was poor under a static culture, but increased dramatically when venous ECs were exposed to shear stress within the vein-chip. This data supports our hypothesis that ACE2 expression (and therefore, SARS-CoV-2 entry into the endothelium) is dependent on venous hemodynamics and the Vein-Chip model is a highly dissectible platform that will help us to unravel the molecular mechanisms that lead to VT and its treatment strategies for COVID-19 and beyond.
