VEGF-C ameliorates lymphatic drainage, portal pressure and ascites in experimental portal hypertension

Abstract

AbstractBackground and aimsGut lymphatic vessels are crucial in maintaining abdominal fluid homeostasis. An impaired lymphatic drainage of these vessels has been associated with the presence of ascites in liver cirrhosis. We thus explored the therapeutic effects of gut-targeted delivery of vascular endothelial growth factor-C (VEGF-C), a pro-lymphangiogenic factor, in cirrhosis and portal hypertension.MethodsVegfr3 antibody-tagged lipocarriers were used to formulate E-VEGF-C molecule for its targeted delivery in lymphatic endothelial cells (LyECs). In vitro characterization, cytotoxicity, in vivo biodistrubution and pharmacokinetic analysis of E-VEGF-C was performed. In vivo, E-VEGF-C was given orally in cirrhotic and non-cirrhotic rat models of portal hypertension. Rats given lipocarriers alone served as vehicle. Mesenteric lymphatic vessels and drainage were analyzed. Ascites and hepatic hemodynamics was measured. Molecular and histological studies of the mesentery was performed. Lymphatic channels were also enumerated in duodenal (D2) biopsies from cirrhotic patients.ResultsE-VEGF-C exhibited a size of <200nm and a zeta potential of 6mV. In vitro and in vivo, E-VEGF-C was efficiently taken up by mesenteric LyECs. E-VEGF-C treated rats displayed an increase in numbers and drainage of mesenteric lymphatic vessels and a reduction in ascites as compared to CCl4-vehicle. Portal pressures were attenuated in both cirrhotic and non-cirrhotic portal hypertensive rats treated with E-VEGF-C as compared to their respective vehicle. In patients’, dilated lymphatic vessels were increased in decompensated as compared to compensated cirrhosis.ConclusionA targeted mesenteric lymphangiogenesis leading to an improved lymphatic drainage may serve as an emerging therapy for portal hypertension and ascites in patients with decompensated cirrhosis.SynopsisA lipid nanocarrier conjugated pro-lymphangiogenic molecule, VEGF-C with specificity for uptake by the gut lymphatic endothelial cells has been developed to enhance gut lymphangiogenesis. A targeted delivery of VEGF-C improves lymphatic vessel drainage, attenuating abdominal ascites and portal pressures. VEGF-C therapy holds immense potential to manage ascites in patients with decompensated cirrhosis having dilated gut lymphatic vessels.