Transcriptome Analysis Reveals the Role of Partial Lymphatic Vessel Ligation in Rats with Cirrhotic Portal Hypertension

The liver lymphatic system plays an essential role during the progression of cirrhotic portal hypertension (PHT), featuring significantly enhanced lymphangiogenesis. However, the role of liver lymphatic functional drainage is understudied in cirrhosis. Therefore, this study aimed to investigate the effects of partial lymphatic vessel ligation (PLVL) of the liver on PHT. The rat model was established by common bile duct ligation (BDL), when PLVL was achieved via ligation of the portal and celiac lymph node. The severity of cirrhosis and PHT were evaluated, as well as macrophage infiltration and lymphangiogenesis. Bulk RNA-seq of liver was used to investigate the underlying mechanisms. Datasets of single-cell and bulk RNA-seq were obtained from the GEO database. Human dermal lymphatic endothelial cells (hLECs) were used for in vitro validation. Ligation of lymphatic drainage caused significant deterioration of liver cirrhosis and PHT in BDL rats. Our bulk RNA-seq suggested significant enrichment of vascular remodeling and angiogenesis-related pathways, as well as lipid metabolism-related biological functions in BDL rats after PLVL. Further analysis combined with public datasets identified several endothelial cell-specific upregulated genes in BDL and PLVL rats. LEC-derived upregulated genes were also identified from bulk RNA-seq of LECs isolated from mice liver, which were validated by incubating hLECs in TNF-α, LPS, TGF-β1. In the current study, we provide the first evidence that liver lymphatic drainage blockade aggravates BDL-induced cirrhotic PHT. LEC-associated secretory proteins might play a potential role in PHT progression, when hepatic inflammation and immune response are considered to be the essential regulatory mechanisms.