With new daily discoveries about the long-term impacts of
COVID-19, there is a clear need to develop in vitro models that can be used to better understand the pathogenicity and impact of
COVID-19. Here, we demonstrate the utility of developing a model of endothelial dysfunction that utilizes human induced pluripotent stem cell-derived endothelial progenitors encapsulated in
collagen hydrogels to study the effects of
COVID-19 on the endothelium. These cells form capillary-like vasculature within 1 week after encapsulation and treating these cell-laden
hydrogels with
SARS-CoV-2 spike protein resulted in a significant decrease in the number of vessel-forming cells as well as vessel network connectivity quantified by our computational pipeline. This vascular dysfunction is a unique phenomenon observed upon treatment with SARS-CoV-2 SP and is not seen upon treatment with other coronaviruses, indicating that these effects were specific to SARS-CoV-2. We show that this vascular dysfunction is caused by an increase in inflammatory
cytokines, associated with the
COVID-19 cytokine storm, released from
SARS-CoV-2 spike protein treated endothelial cells. Following treatment with the
corticosteroid dexamethasone, we were able to prevent
SARS-CoV-2 spike protein-induced endothelial dysfunction. Our results highlight the importance of understanding the interactions between
SARS-CoV-2 spike protein and the endothelium and show that even in the absence of immune cells, the proposed 3D in vitro model for angiogenesis can reproduce COVID-19-induced endothelial dysfunction seen in clinical settings. This model represents a significant step in creating physiologically relevant disease models to further study the impact of
long COVID and potentially identify mitigating
therapeutics.