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Here, we demonstrate the utility of developing a model of endothelial dysfunction that utilizes human induced pluripotent stem cell\u2010derived endothelial progenitors encapsulated in collagen hydrogels to study the effects of COVID\u201019 on the endothelium. These cells form capillary\u2010like vasculature within 1 week after encapsulation and treating these cell\u2010laden hydrogels with SARS\u2010CoV\u20102 spike protein resulted in a significant decrease in the number of vessel\u2010forming cells as well as vessel network connectivity quantified by our computational pipeline. This vascular dysfunction is a unique phenomenon observed upon treatment with SARS\u2010CoV\u20102 SP and is not seen upon treatment with other coronaviruses, indicating that these effects were specific to SARS\u2010CoV\u20102. We show that this vascular dysfunction is caused by an increase in inflammatory cytokines, associated with the COVID\u201019 cytokine storm, released from SARS\u2010CoV\u20102 spike protein treated endothelial cells. Following treatment with the corticosteroid dexamethasone, we were able to prevent SARS\u2010CoV\u20102 spike protein\u2010induced endothelial dysfunction. Our results highlight the importance of understanding the interactions between SARS\u2010CoV\u20102 spike protein and the endothelium and show that even in the absence of immune cells, the proposed 3D\n                    <jats:italic>in vitro<\/jats:italic>\n                    model for angiogenesis can reproduce COVID\u201019\u2010induced 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.\n                  <\/jats:p>","DOI":"10.1002\/jbm.a.37543","type":"journal-article","created":{"date-parts":[[2023,4,8]],"date-time":"2023-04-08T07:04:45Z","timestamp":1680937485000},"page":"524-533","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["<scp>SARS\u2010CoV<\/scp>\n                    \u20102 spike protein induces endothelial dysfunction in\n                    <scp>3D<\/scp>\n                    engineered vascular networks"],"prefix":"10.1002","volume":"112","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4336-6072","authenticated-orcid":false,"given":"Brett","family":"Stern","sequence":"first","affiliation":[{"name":"The University of Texas at Austin Department of Biomedical Engineering  Austin Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Monteleone","sequence":"additional","affiliation":[{"name":"The University of Texas at Austin, Dell Medical School Department of Internal Medicine  Austin Texas USA"},{"name":"Department of Internal Medicine Ascension Texas Cardiovascular  Austin Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Janet","family":"Zoldan","sequence":"additional","affiliation":[{"name":"The University of Texas at Austin Department of Biomedical Engineering  Austin Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2023,4,8]]},"reference":[{"key":"e_1_2_9_2_1","unstructured":"Organization W. 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