Abstract
The vascular barrier is heavily injured following SARS-CoV-2 infection and contributes enormously to life-threatening complications in COVID-19. This endothelial dysfunction is associated with the phlogistic phenomenon of cytokine storms, thrombotic complications, abnormal coagulation, hypoxemia, and multiple organ failure. The mechanisms surrounding COVID-19 associated endotheliitis have been widely attributed to ACE2-mediated pathways. However, integrins are emerging as possible receptor candidates for SARS-CoV-2, and their complex intracellular signaling events are essential for maintaining endothelial homeostasis. Here, we showed that the spike protein of SARS-CoV-2 depends on its RGD motif to drive barrier dysregulation by hijacking integrin αVβ3, expressed on human endothelial cells. This triggers the redistribution and internalization of major junction protein VE-Cadherin which leads to the barrier disruption phenotype. Both extracellular and intracellular inhibitors of integrin αVβ3 prevented these effects, similarly to the RGD-cyclic peptide compound Cilengitide, which suggests that the spike protein-through its RGD motif-binds to αVβ3 and elicits vascular leakage events. These findings support integrins as an additional receptor for SARS-CoV-2, particularly as integrin engagement can elucidate many of the adverse endothelial dysfunction events that stem from COVID-19.
Keywords: Cilengitide; RGD motif; SARS-CoV-2 variants of concern; integrin αVβ3; vascular dysfunction.
【저자키워드】 SARS-CoV-2 variants of concern, vascular dysfunction, RGD motif, cilengitide, integrin αVβ3, 【초록키워드】 COVID-19, SARS-CoV-2, Thrombotic complications, SARS-COV-2 infection, SARS-CoV-2 variant, peptide, Spike protein, Endothelial dysfunction, Endotheliitis, Protein, SARS-CoV-2 variants, endothelial cells, Integrins, Hypoxemia, Complication, phenotype, vascular dysfunction, receptor, multiple organ failure, inhibitor, mechanism, homeostasis, cilengitide, integrin, Pathways, Trigger, Cytokine storms, dysregulation, Support, endothelial, Vascular, complex, abnormal coagulation, thrombotic, life-threatening, candidate, internalization, cadherin, redistribution, vascular leakage, motif, intracellular signaling, Effects, event, Extracellular, events, contribute, the spike protein, expressed, elicit, prevented, phlogistic, 【제목키워드】 SARS-CoV-2, barrier, integrity, Loss,