Serum from COVID-19 patients promotes endothelial cells activation through protease-activated receptor 2

Endothelial dysfunction plays a central role in the pathophysiology of COVID-19 and is closely linked to the severity and mortality of the disease. The inflammatory response to infection can alter the capacity of the endothelium to regulate vascular tone, immune responses, and the balance between anti-thrombotic and pro-thrombotic properties. However, the specific endothelial pathways altered during COVID-19 are not yet fully understood. In this study, we sought to identify molecular changes in endothelial cells induced by circulating factors characteristic of COVID-19. To this aim, we cultured endothelial cells with serum from patients with COVID-19 or non-COVID-19 pneumonia. Through transcriptomic analysis, we were able to identify a distinctive endothelial phenotype that is induced by COVID-19 patient serum in the lack of endothelial infection This phenotype is characterized by increased apoptosis and the up-regulation of several immune response-related molecules, some of which are implicated in hypercoagulability. Our findings suggest that these effects are mediated, at least in part, by protease-activated receptor 2 (PAR-2), as predicted by transcriptome network analysis and validated in vitro using PAR-2 specific modulators.

内皮功能障碍在新冠病毒病（COVID-19）的病理生理学中发挥核心作用，且与该疾病的严重程度及死亡率密切相关。机体针对感染产生的炎症反应可改变内皮细胞调控血管张力、免疫应答以及抗血栓与促血栓特性平衡的能力。然而，新冠病毒病感染过程中发生异常改变的特定内皮通路尚未完全阐明。本研究旨在明确新冠病毒病特征性循环因子诱导的内皮细胞分子变化。为此，我们将内皮细胞与新冠病毒病患者或非新冠病毒病肺炎患者的血清共培养。通过转录组学分析，我们成功鉴定出一种独特的内皮表型：该表型在内皮细胞未被感染的情况下，可由新冠病毒病患者血清诱导产生，其特征为细胞凋亡增加以及多种免疫应答相关分子的上调，其中部分分子与高凝状态相关。我们的研究结果表明，这些效应至少部分由蛋白酶激活受体2（PAR-2）介导，这一结论得到了转录组网络分析的预测，并通过使用PAR-2特异性调节剂进行的体外实验得到了验证。