Platelet activation relieves liver portal hypertension via the lymphatic system though the classical vascular endothelial growth factor receptor 3 signaling pathway

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BACKGROUND: Liver cirrhosis and portal hypertension (PHT) can lead to lymphatic abnormalities and coagulation dysfunction. Because lymphangiogenesis may relieve liver cirrhosis and PHT, the present study investigated the gene expression alterations in the lymphatic system and the effectiveness of platelet-mediated lymphangiogenesis in improving liver cirrhosis and PHT. AIM: To investigate the role of lymphangiogenesis in preclinical PHT models. METHODS: Immunohistochemistry and transcriptome sequencing of bile duct ligation (BDL) and control lymphatic samples were conducted to reveal the indicated signaling pathways. Functional enrichment analyses were performed on the differentially expressed genes and hub genes. Adenoviral infection of vascular endothelial growth factor C (VEGF-C), platelet-rich plasma (PRP), and VEGF3 receptor (VEGFR) inhibitor MAZ-51 was used as an intervention for the lymphatic system in PHT models. Histology, hemodynamic tests and western blot analyses were performed to demonstrate the effects of lymphatic intervention in PHT patients. RESULTS: Lymphangiogenesis was increased in the BDL rat model. Transcriptome sequencing analysis of the extrahepatic lymphatic system revealed its close association with platelet adherence, aggregation, and activation. The role of PHT in the rat model was investigated by activating (PRP) and inhibiting (MAZ-51) the lymphatic system. PRP promoted lymphangiogenesis, which increased lymphatic drainage, alleviated portal pressure, reduced liver fibrosis, inhibited inflammation, inhibited angiogenesis, and suppressed mesenteric artery remodeling. MAZ-51 reversed the above improvements. CONCLUSION: VEGF-C/VEGFR-3, platelets impede fibrosis, angiogenesis, and mesenteric artery remodeling, ultimately alleviating PHT. Thus, platelet intervention is a therapeutic approach for cirrhosis and PHT.

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