Vascular dysregulation following SARS-CoV-2 infection involves integrin signalling through a VE-Cadherin mediated pathway

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 have emerged 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 through hijacking integrin αVβ3. 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.

Comparative Assessment of the Inhibitory Potential of the Herbicide Glyphosate and Its Structural Analogs on RGD-Specific Integrins Using Enzyme-Linked Immunosorbent Assays

“…However, this integrin is not present in resting endothelial cells and most normal organ systems, making it a suitable target for anti-angiogenic therapy [ 52 ]. The SARS-CoV-2 spike protein receptor binding domain (SARS-CoV-2 S protein) interacts with αVβ3 via the RGD motif and causes events of vascular leakage; thus, integrins’ interactions can explain several COVID-19-induced events of endothelial dysfunction [ 53 ]. Glyphosate is an efficient inhibitor if RGD is the obligate binding site.…”