Recombinant VEGF-C restores mesenteric lymphatic drainage and improves gut immune surveillance in experimental cirrhosis

Abstract Gut lymphatic vessels (LVs) are crucial for maintaining gut immunity and abdominal fluid homeostasis. In experimental liver cirrhosis with ascites, gut LVs are dilated and dysfunctional with impaired gut immune response. Therapy with pro-lymphangiogenic factor, vascular endothelial growth factor-C (VEGF-C) promotes functional LVs growth and attenuates inflammation. However, therapeutic role of VEGF-C in cirrhosis has not been explored. Here we developed a nanoformulation comprising of recombinant human VEGF-C loaded reverse micelles (E-VEGF-C) and delivered it orally in rat models of liver cirrhosis to specifically target mesenteric LVs (mLVs). E-VEGF-C treated cirrhotic rats displayed an increased density of gut LVs, improved functional drainage and reduced abdominal fluid/ascites and portal pressures without any adverse events. E-VEGF-C also enhanced the proliferation of LVs in the mesenteric lymph nodes, triggering active immune responses, which helped to contain the spreading of bacteria to other organs preventing systemic infection. At molecular level, E- VEGF-C treatment upregulated the expression of cell adhesion and permeability markers, VE-cadherin and VCAM1 in the mesenteric lymphatic endothelial cells. Collectively, oral delivery of E-VEGF-C in cirrhotic rats ameliorates drainage of gut LVs, ascites formation and immunity and thus represents a potential treatment to manage ascites and immune dysfunction in cirrhosis.