Disrupted endothelial permeability plays a crucial role in the vasculitis pathogenesis of Kawasaki disease (KD), which leads to pathological vascular leak and facilitates inflammatory cell infiltration in vascular lesions; however, the mechanisms involved in the development of endothelial barrier dysfunction during KD vasculitis are still largely unclear. Here, we found that sera from patients with KD can induce endothelial cell (EC) hyperpermeability compared to sera from healthy controls. We observed that serum vascular endothelial growth factor (VEGF) levels were increased in KD patients and sera from KD patients upregulated the expression of VEGF receptor 2 (VEGFR2) and neuropilin-1 (NRP1) in human coronary artery endothelial cells (HCAECs). Intriguingly, compared with silence of VEGFR2 in HCAECs, NRP1 silence resulted in a marked decrease in EC permeability. Furthermore, soluble NRP1 (sNRP1) remarkably reduced the stimulation of EC permeability by sera from KD patients compared with bevacizumab treatment. Importantly, we showed that besides VEGF, angiopoietin-like-4 (ANGPTL4), a NRP1-binding vasoactive factor, was also increased in KD and contributed to the EC permeability in KD conditions. In addition, levels of both ANGPTL4 and VEGF were inversely correlated with albumin levels in the serum of KD patients. Collectively, the data demonstrated that overexpressed NRP1, along with upregulated VEGFR2, in HCAECs treated with KD sera promotes endothelial permeability via interaction with the increased ANGPTL4 and VEGF in KD. Neutralization of hyperpermeability factors by sNRP1 may be a novel therapeutic strategy for KD vasculitis.

中文翻译：

---

内皮细胞中过表达的 Neuropilin-1 通过与川崎病中的 ANGPTL4 和 VEGF 相互作用促进内皮通透性

破坏的内皮通透性在川崎病（KD）的血管炎发病机制中起着至关重要的作用，导致病理性血管渗漏并促进血管病变中的炎性细胞浸润；然而，在 KD 血管炎期间内皮屏障功能障碍发展的机制仍不清楚。在这里，我们发现与健康对照的血清相比，来自 KD 患者的血清可以诱导内皮细胞 (EC) 高渗透性。我们观察到 KD 患者血清血管内皮生长因子 (VEGF) 水平升高，KD 患者血清上调人冠状动脉内皮细胞 (HCAECs) 中 VEGF 受体 2 (VEGFR2) 和神经纤毛蛋白-1 (NRP1) 的表达。有趣的是，与 HCAECs 中 VEGFR2 的沉默相比，NRP1 沉默导致 EC 通透性显着降低。此外，与贝伐单抗治疗相比，可溶性 NRP1 (sNRP1) 显着降低了 KD 患者血清对 EC 通透性的刺激。重要的是，我们发现除了 VEGF，血管生成素样 4 (ANGPTL4)，一种 NRP1 结合血管活性因子，在 KD 中也增加，并有助于 KD 条件下的 EC 通透性。此外，ANGPTL4 和 VEGF 的水平与 KD 患者血清中的白蛋白水平呈负相关。总的来说，数据表明，在用 KD 血清处理的 HCAEC 中，过表达的 NRP1 以及上调的 VEGFR2 通过与 KD 中增加的 ANGPTL4 和 VEGF 相互作用来促进内皮通透性。sNRP1 中和高渗透性因子可能是 KD 血管炎的一种新的治疗策略。