The receptor tyrosine kinase EphB4 and its ligand EphrinB2 (EFNB2) play a critical role in vasculature development. The disruption of endothelial cellular homeostasis may have a crucial role in the pathogenesis of early KD vasculitis and may potentially be responsible for the development of coronary artery outcomes. In response to these stimuli, monocytes and neutrophils from peripheral blood are recruited into stimulated vascular cells. In addition, a large number of damage-related molecular patterns (DAMPs) generated by cell death and oxidative stress in circulating blood have multipotent effects on platelets, monocytes, neutrophils, T cells, endothelial cells, and vascular smooth muscle cells. Therefore, superantigens can activate T cells at a very low concentration, thus secreting a large number of cytokines, leading to immune disorders. That is, innate immune pathogen-associated molecular patterns (PAMPs) from microorganisms activate pro-inflammatory signals in innate immune cells and blood vessel cells, leading to abnormal activation of the body’s immune system. A common hypothesis is that the pathogenesis of Kawasaki disease may be related to a superantigenic toxin mechanism. The cause and pathogenesis of KD remain unknown. Although the application of intravenous immunoglobulin (IVIG) decreases the incidence of coronary artery aneurysms, about 4% of patients are still not cured. Thus, the COVID-19 outbreak brought more attention to KD, and more people started to think about what kind of disease it is and how to cure it. Therefore, some have warned that KD may be one of the important complications of SARS-CoV-2 in children. Several reports suggest that children infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may develop a type of multisystem vasculitis, and this multisystem inflammation has a lot in common with KD. Nowadays, the pandemic caused by the novel coronavirus COVID-19 has become an urgent public event of global concern. In the past, although KD has surpassed rheumatic fever to become the most common cause of acquired heart disease in children, public understanding of KD and research into its treatment were inadequate. Cardiovascular manifestations can be prominent during the acute KD episode and are the leading cause of long-term morbidity and mortality. Kawasaki disease (KD) is an acute, self-limited febrile illness characterized by systemic inflammation in all medium-sized arteries. The results reveal that EphrinB2-Fc has a protective function in endothelial cells and has promising clinical applications for protecting vascular endothelium in patients with KD. EphrinB2-Fc treatment of KD sera-activated HCAECs suppressed cell proliferation, reduced the expression of inflammation-related factors (such as IL-6 and P-selectin), and elevated cell angiogenesis ability. The EphB4 protein levels in the CECs of CAA+ KD patients were much lower than those in healthy children. Our study showed that EphB4 showed low expression in both KD patients and the cell model of KD. The cell migration, angiogenesis, and proliferation ability were assessed, and the expression of inflammation-related factors was measured. The overexpression of EphB4 or treatment with EphrinB2-Fc was found to intervene in the cell model. Human coronary artery endothelial cells (HCAECs) were stimulated with sera from acute KD patients to establish the KD cell model. The levels of EphB4 were compared between KD patients and healthy children. Hence, this study aimed to explore the role of EphrinB2/EphB4 and the potential therapeutic effect of EphrinB2-Fc in the coronary arterial endothelial injury of KD. However, little is known about EphrinB2/EphB4 in the pathogenesis of Kawasaki disease (KD) and coronary artery aneurysm formation. The EphrinB2/EphB4 signaling pathway involves the regulation of vascular morphogenesis and angiogenesis.
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