血管成纤维细胞来源平足蛋白通过调控血小板S1P/S1PR1通路促进大动脉炎血管纤维化的机制研究

大动脉炎可以导致靶器官严重缺血和功能衰竭，慢性进展的血管纤维化是其最重要的病理生理变化，尚无有效治疗手段，而血管成纤维细胞异常活化是其中的关键环节。既往报道成纤维细胞来源平足蛋白（PDPN）能够激活血小板，而主要由血小板生成的1-磷酸鞘氨醇（S1P）能够促进成纤维细胞活化，但成纤维细胞与血小板之间的相互调控在大动脉炎发病机制中尚无研究。我们前期发现，大动脉炎中血管成纤维细胞高度表达PDPN和S1P受体S1PR1，患者血小板增多并与血管病变进展有关，血小板来源S1P增多，且S1P能够促进血管成纤维细胞生成PDPN。故而我们提出如下假说：大动脉炎发病过程中，血管成纤维细胞来源PDPN通过激活血小板促进S1P生成，异常活化血小板来源的S1P通过结合S1PR1促进血管成纤维细胞生成包括PDPN在内的纤维化相关因子，从而形成血管成纤维细胞与血小板之间正反馈通路，导致大动脉炎血管纤维化不断进展。

Takayasu arteritis (TAK) can induce severe ischemia and functional failure of target organs. Chronic progressing vascular fibrosis is the most important pathophysiological feature in TAK, without effective treatment, and abnormal activation of vascular fibroblasts is the key point in this process. Fibroblast-derived podoplanin (PDPN) has been reported to activate platelets, and sphingosine-1-phosphate (S1P), mainly produced by platelets, can promote fibroblast activation. The role of interaction between fibroblasts and platelets in the pathogenesis of Takayasu arteritis has not been studied. In previous research, we found that vascular fibroblasts highly expressed PDPN and S1P receptor 1 (S1PR1) in Takayasu arteritis. Platelets were significantly increased in TAK, which was related to the progression of vascular injury. The level of S1P derived from platelets also raised, and S1P could promote the production of PDPN by vascular fibroblasts. Therefore, we propose the following hypothesis: In the course of TAK, on the one hand, PDPN derived from vascular fibroblasts activates platelets and promotes S1P production; on the other hand, excessive S1P, derived from activated platelet, promotes fibroblasts to product fibrosis-related factors including PDPN by binding to S1PR1. The positive feedback between fibroblasts and platelets leads to the continuous progression of vascular fibrosis in TAK.