Interferon (IFN) alpha (IFNα) and lambda3 (IFNλ3) constitute first line responses of immunity against SARS-CoV-2 infection by increasing interferon-stimulated genes (ISGs). Prolonged IFN production may exacerbate inflammation, contributing to endotheliitis and vascular dysfunction in COVID-19. We investigated whether spike protein S1 (SP1) of SARS-CoV-2 via IFN influences inflammation in human vascular and lymphatic endothelial cells (EC) and whether these processes contribute to vascular dysfunction in the context of hypertension. We focused on ISG15, a crucial immune protein that is also implicated in hypertension-associated vascular injury.