Abstract The vasculature is heavily impacted by SARS-CoV-2 infection. Conflicting results exist concerningthe mechanisms by which the SARS-CoV-2 virus acts on the vasculature. The presence of the virus within endothelial cells has been reported in patient samples. However, the ACE2 receptor wasnot detected in endothelial cells when analyzed by RNAseq analysis. Thus, how SARS-CoV-2 contributes to vascular inflammation and whether cross-talk between epithelial cells and endothelial cells is involvedare unclear. Therefore, we investigated the interaction between SARS-CoV-2 and the vasculature using 2D and 3D in vitro models, as well asour previously developed 3D vesseloid model. We first determined the suitability of the 3D vesseloid model for our study and then assessed whether SARS-CoV-2 is able to directly infect endothelial cells. In the absence of ACE2 in endothelial cells, no infection was detected. When ACE2 was overexpressed in endothelial cells, low uptake of viral particles by endothelial cells was observed without efficient viral production. We then explored the possibility that an indirect effect of SARS-CoV-2 infection involvesepithelial-endothelial cellcross-talk. After infection of the epithelial cells, a significant inflammatory response was detected in the endothelial cells. Furthermore, we investigated the cytokines possibly implicated and identified CXCL10 as the most highly expressed proinflammatorycytokine and explored its function in this context. Finally, the clinical relevance of our findings was confirmed by evaluating CXCL10 and alternative cytokine dosages in blood samples fromSARS-CoV-2-infected patients, which were validated in silico in an independent patient cohort.