Abstract
Vascular endothelial cells (ECs) form a critical interface between blood and tissues that maintains whole-body homeostasis. In COVID-19, disruption of the EC barrier results in edema, vascular inflammation, and coagulation, hallmarks of this severe disease. However, the mechanisms by which ECs are dysregulated in COVID-19 are unclear. Here, we show that the spike protein of SARS-CoV-2 alone activates the EC inflammatory phenotype in a manner dependent on integrin ⍺5β1 signaling. Incubation of human umbilical vein ECs with whole spike protein, its receptor-binding domain, or the integrin-binding tripeptide RGD induced the nuclear translocation of NF-κB and subsequent expression of leukocyte adhesion molecules (VCAM1 and ICAM1), coagulation factors (TF and FVIII), proinflammatory cytokines (TNFα, IL-1β, and IL-6), and ACE2, as well as the adhesion of peripheral blood leukocytes and hyperpermeability of the EC monolayer. In addition, inhibitors of integrin ⍺5β1 activation prevented these effects. Furthermore, these vascular effects occur in vivo, as revealed by the intravenous administration of spike, which increased expression of ICAM1, VCAM1, CD45, TNFα, IL-1β, and IL-6 in the lung, liver, kidney, and eye, and the intravitreal injection of spike, which disrupted the barrier function of retinal capillaries. We suggest that the spike protein, through its RGD motif in the receptor-binding domain, binds to integrin ⍺5β1 in ECs to activate the NF-κB target gene expression programs responsible for vascular leakage and leukocyte adhesion. These findings uncover a new direct action of SARS-CoV-2 on EC dysfunction and introduce integrin ⍺5β1 as a promising target for treating vascular inflammation in COVID-19.
Keywords: ACE2; COVID-19; NF-κB; SARS-CoV-2; endothelial cell; endothelial dysfunction; inflammation; integrin; permeability; spike protein.
【저자키워드】 COVID-19, SARS-CoV-2, Inflammation, ACE2, Endothelial dysfunction, spike protein., NF-κB, Endothelial cell, integrin, permeability, 【초록키워드】 Cytokines, IL-6, lung, inhibitors, Spike protein, Endothelial dysfunction, Coagulation, Peripheral blood, kidney, Receptor-binding domain, endothelial cells, edema, Coagulation factors, proinflammatory cytokines, in vivo, inhibitor, Incubation, expression, Critical, liver, mechanism, homeostasis, Blood, NF-κB, leukocytes, Endothelial cell, IL-1β, Signaling, administration, integrin, permeability, severe disease, Capillaries, intravitreal injection, intravenous, target gene, leukocyte, coagulation factor, Intravenous administration, umbilical vein, Adhesion Molecule, dysfunction, Proinflammatory cytokine, endothelial, Activation, increased expression, tissue, tissues, domain, nuclear translocation, vascular endothelial cells, TNFα, inflammatory phenotype, CD45, hallmark, vascular leakage, adhesion, spike protein of SARS-CoV-2, hallmarks, vascular inflammation, motif, ICAM1, VCAM1, FVIII, peripheral blood leukocytes, Effects, bind, responsible, subsequent, addition, occur, the spike protein, dependent on, the receptor-binding domain, maintain, activate, prevented, dysregulated, peripheral blood leukocyte, umbilical, vascular effect, 【제목키워드】 endothelial, NF-κB signaling, induce,