S1PR1在心梗后心室重构过程中对淋巴管系统稳态的影响和机制研究

改善心梗后心室重构是防治心衰的关键，淋巴管系统调节流体平衡在心脏重塑中发挥重要作用。我们前期研究发现心梗后淋巴管内皮细胞（LEC）1-磷酸鞘氨醇1型受体（S1PR1）表达降低，S1PR1拮抗剂破坏LEC缝隙连接、降低其迁移能力，S1PR1激动剂降低小鼠心梗后心肌水肿，经大数据分析并结合文献，我们提出S1PR1在Gi/PLC和Rac GTP酶介导下调控淋巴管新生和通透性，改善心梗后组织水肿和心室重构。拟建立淋巴管内皮细胞S1PR1特异性敲除小鼠，采用淋巴造影术、免疫荧光染色、小动物心脏超声等分析LEC S1PR1对心梗后淋巴管稳态和心室重构影响，同时辅以分子生物学、跨内皮电阻测量等实验研究S1PR1对LEC 功能的影响和分子机制。有望揭示S1P/S1PR1信号通过调控淋巴管稳态在心梗后心室重构起重要作用，以期针对淋巴系统找到改善心室重构新靶点，为临床心梗后治疗提供重要理论依据。

To improve ventricular remodeling is the key of prevention and treatment of heart failure after myocardial infarction (MI). Lymphatic system plays an important role in regulating of fluid balance in myocardial remodeling after myocardial infarction. We have found that the expression of S1P receptor 1 (S1PR1) mRNA levels were decreased in lymphatic endothelial cell (LEC) after MI, and that S1PR1 antagonist destroyed the gap junction of LECs and decreased LEC cell migration, and that S1PR1 agonists alleviated the myocardial edema after MI in mice. It was reported that S1PR1 regulated endothelial cell permeability and angiogenesis via Rac GTPase and Gi/PLC, respectively. The previous findings and our preliminary data suggest that LEC S1PR1 regulates lymphatic vessels permeability and lymphangiogenesis via Gi/PLC and Rac GTPase, leading to postoperative myocardial edema and ventricular remodeling. In this study, the effects of S1PR1 on LEC barrier function and permeability and its mechanism were studied by molecular biology, immunofluorescence technique, trans-endothelial resistance measurement and glutathione (GST) pull- Rac activity. We plan to use LEC S1PR1 specific conditional knockout mice to address the role of LEC S1PR1 for lymphatic remodeling and cardiac modeling after MI by lymphatic angiography, immunostaining, and cardiac ultrasound .This project is expected to reveal that S1P/S1PR1 signaling plays an important role in the regulation of lymphatic homeostasis after myocardial infarction, and aims to find a new target for improving ventricular remodeling via enhancing lymphangiogenesis and lymph integrity providing an important theoretical basis for clinical treatment after myocardial infarction.