Liu Ji-Ting, Bao Han, Fan Yang-Jing, Li Zi-Tong, Yao Qing-Ping, Han Yue, Zhang Ming-Liang, Jiang Zong-Lai, Qi Ying-Xin
Institute of Mechanobiology and Medical Engineering, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China.
Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai Diabetes Institute, Shanghai Clinical Center for Diabetes, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Key Clinical Center for Metabolic Disease, Shanghai, China.
Front Cell Dev Biol. 2021 Sep 16;9:744320. doi: 10.3389/fcell.2021.744320. eCollection 2021.
Phenotypic switch of vascular smooth muscle cells (VSMCs) is important in vascular remodeling which causes hyperplasia and restenosis after intimal injury. Platelets are activated at injured intima and secrete platelet-derived microvesicles (PMVs). Herein, we demonstrated the role of PMVs in VSMC phenotypic switch and the potential underlying mechanisms. , platelets were locally adhered and activated at intimal injury site, while Lamtor1 was promoted and VSMCs were dedifferentiated. PMVs, collected from collagen-activated platelets which mimicked collagen exposure during intimal injury, promoted VSMC dedifferentiation, induced Lamtor1 expression, and activated mTORC1 signaling, reflected by the phosphorylation of two downstream targets, i.e., S6K and 4E-BP1. Knockdown of Lamtor1 with small interfering RNA attenuated these processes induced by PMVs. Based on the previously published proteomic data, Ingenuity Pathway Analysis revealed that Src may participate in regulating effects of PMVs. Src inhibitor significantly reversed the effects of PMVs on VSMC dedifferentiation, Lamtor1 expression and mTORC1 activation. Furthermore, in SMC-specific knockout mice, intimal hyperplasia was markedly attenuated after intimal injury compared with the wild type. Our data suggested that PMVs secreted by activated platelets promoted VSMC dedifferentiation Src/Lamtor1/mTORC1 signaling pathway. Lamtor1 may be a potential therapeutic target for intimal hyperplasia after injury.
血管平滑肌细胞（VSMCs）的表型转换在血管重塑中起重要作用，血管重塑会导致内膜损伤后增生和再狭窄。血小板在内膜损伤处被激活并分泌血小板衍生微泡（PMVs）。在此，我们证明了PMVs在VSMC表型转换中的作用及其潜在的机制。在内膜损伤部位，血小板局部黏附并被激活，同时Lamtor1被上调，VSMCs发生去分化。从模拟内膜损伤时胶原暴露的胶原激活血小板中收集的PMVs促进了VSMC去分化，诱导了Lamtor1表达，并激活了mTORC1信号通路，这可通过两个下游靶点即S6K和4E-BP1的磷酸化反映出来。用小干扰RNA敲低Lamtor1可减弱PMVs诱导的这些过程。基于先前发表的蛋白质组学数据， Ingenuity通路分析显示Src可能参与调节PMVs的作用。Src抑制剂显著逆转了PMVs对VSMC去分化、Lamtor1表达和mTORC1激活的影响。此外，在平滑肌细胞特异性敲除小鼠中，与野生型相比，内膜损伤后内膜增生明显减轻。我们的数据表明，活化血小板分泌的PMVs通过Src/Lamtor1/mTORC1信号通路促进VSMC去分化。Lamtor1可能是损伤后内膜增生的一个潜在治疗靶点。
