S-Allyl-Cysteine Ameliorates Cirrhotic Portal Hypertension by Enhancing Lymphangiogenesis via a VEGF-C-Independent Manner

Abstract

Background and Aims

Lymphangiogenesis is enhanced during the development of liver cirrhosis and portal hypertension (PHT). However, hepatic lymphatic vascular system is understudied in liver cirrhosis and PHT. Hydrogen sulfide (H₂S) and related compounds have potential prolymphangiogenic effects besides its previously reported vascular-protective effects. Therefore, we aimed to investigate the effects of endogenous H₂S donor S-allyl-cysteine (SAC) on bile duct ligation (BDL)-induced liver cirrhosis and PHT.

Methods

BDL rats with cholestatic liver cirrhosis and PHT were orally administrated with SAC at 100 or 200 mg/kg/day, as well as DL-propargylglycine (PAG) or MAZ-51 injections. Hemodynamic parameters were determined, and subsequent evaluations of liver fibrosis, intrahepatic vascular resistance (IHVR) and lymphangiogensis were performed. Human lymphatic endothelial cells (hLECs) were used for in vitro verification of prolymphangiogenic effects of SAC.

Results

SAC treatment significantly decreased PP and promoted endogenous H₂S production. Liver fibrosis and IHVR were also ameliorated. Hepatic and mesenteric lymphangiogenesis were enhanced in BDL rats and further promoted by SAC despite a significant downregulation of hepatic VEGF-C. Inhibition of H₂S production by PAG significantly reduced lymphatic vessels, while inhibition of lymphangiogensis by MAZ-51 reversed the protective effects of SAC against PHT. SAC enhanced lymphangiogenic functions in vitro by promoting cellular H₂S production and activating Akt phosphorylation without altering VEGF-C/D, which were reversed by PAG and MAZ-51.

Conclusions

SAC significantly alleviated BDL-induced liver cirrhosis and PHT. Meanwhile, elevated H₂S induced by SAC facilitated lymphangiogenesis via a VEGF-C-independent manner, which contributed to the alleviation of PHT.