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

Objective: Gut lymphatic vessels are crucial in maintaining abdominal fluid homeostasis. We studied these vessels in clinical cirrhosis and explored effects of vascular endothelial growth factor-C (VEGF-C), a pro-lymphangiogenic factor, in experimental portal hypertension. Design: Vascular endothelial growth factor receptor 3 (vegfr3)-positive lymphatic channels were enumerated in duodenal (D2) biopsies from cirrhotic patients. Vegfr3 antibody-tagged lipid nanocarriers were used to formulate novel nano-engineered (E-VEGF-C) molecule for targeted lymphangiogenesis of gut lymphatic vessels. The uptake of E-VEGF-C was evaluated in lymphatic endothelial cells (LyECs) in vitro and in vivo. The effects of E-VEGF-C were tested in cirrhotic and non-cirrhotic animal models of portal hypertension. Animals given nanocarriers alone served as vehicle. Mesenteric lymphatic vessel numbers/proliferation and drainage were analyzed. Abdominal ascites, hepatic and systemic hemodynamics was measured. Liver, duodenum, mesentery and plasma were examined. Results: In D2 biopsies, number of dilated vegfr3+ lymphatic vessels was significantly increased in decompensated as compared to compensated cirrhosis and correlated with presence of ascites. E-VEGF-C was efficiently taken up by the mesenteric LyECs. E-VEGF-C treated rats displayed a marked increase in the proliferation of mesenteric lymphatic vessels and drainage as compared to CCl4-vehicle. Ascites and mesenteric inflammation were markedly reduced in E-VEGF-C treated cirrhotic rats. Portal pressures were attenuated in both cirrhotic and non-cirrhotic portal hypertensive rats treated with E-VEGF-C as compared to respective vehicle groups. Conclusion: E-VEGF-C molecule enhances mesenteric lymphangiogenesis and improves lymphatic vessel drainage, attenuating abdominal ascites and portal pressures. Targeted gut lymphangiogenesis may serve as an emerging therapy for portal hypertension.

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