Spike 1 protein of SARS-CoV-2 induces endothelial inflammation and vascular dysfunction through interferon ISG15-dependent mechanisms
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ID: 314120
2026
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Abstract
AIMS: 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. METHODS AND RESULTS: Exposure of microvascular ECs to SP1 of SARS-CoV-2 induced expression of ISGs: ISG15, MX1 and IFIT1. These effects were potentiated by IFNs and reduced by ADAM17 and STAT1 inhibition and genetic inhibition of IFN alpha and beta receptor subunit 1 (IFNAR1). In microvascular ECs IFNλ3 and IFNα increased expression of ISGs, TMPRSS2, ADAM17, production of pro-inflammatory mediators (TNFα, IL-6, PAI-1) and reduced phosphorylation of eNOS (Ser1177). In pulmonary, lymphatic and aortic ECs, IFNα, but not IFNλ3, increased expression of ISGs and IL-6. To explore the relevance in intact vessels, effects of IFNs were studied in isolated microvessels from wildtype (WT), hypertensive and ISG15-/- mice. IFNα, IFNλ3 and SP1 reduced endothelium-dependent relaxation in WT vessels, whereas IFNα increased contraction in vessels from hypertensive mice. Vascular dysfunction induced by IFNα, IFNλ3 or spike protein was abrogated in vessels from ISG15-/- mice. CONCLUSIONS: SP1 and IFNs synergically increase EC expression of ISGs through ADAM17. IFNλ3 and IFNα promote endothelial inflammation and vascular dysfunction through ISG15. These processes may play a role in the endotheliopathy and vascular damage associated with SP1 and might contribute to cardiovascular sequelae, including hypertension, of SARS-CoV-2 infection.
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| Authors | Francisco J. Rios, Augusto C. Montezano, Lívia L. Camargo, Rhéure Alves-Lopes, Ana B. García‐Redondo, Elihú Aranday-Cortés, Ana M. Briones, John McLauchlan, Rhian M. Touyz |
| Journal | cardiovascular research |
| Year | 2026 |
| DOI |
10.1093/cvr/cvag111
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| URL | |
| Keywords | Keywords not found |
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