SUMMARY The lymphatic system maintains tissue fluid homeostasis and regulates local inflammatory responses.1,2 The liver lymphatic system remains poorly understood. The goal of this proposed research is to advance our understanding of the mechanisms of hepatic lymphangiogenesis (the formation of new lymphatic vessels) and the role of lymphatic vessels in liver pathophysiology. Vascular endothelial growth factor C (VEGF-C) is the major inducer of lymphangiogenesis. Our preliminary studies have shown that enhanced hepatic lymphangiogenesis by VEGF-C overexpression reduces liver fibrosis, suggesting a therapeutic potential. Additional data show that Schwann cells of hepatic sympathetic nerves play a central role in hepatic lymphangiogenesis as a source of VEGF-C and as a recruiter of macrophages, which may contribute to hepatic lymphangiogenesis by producing fibronectin-1 (FN1), a substrate for integrins essential for VEGF-C/VEGF receptor 3 (VEGFR3) signaling. We thus hypothesize that lymphatic ablation should increase inflammation and promote disease progression, and lymphangiogenesis driven by Schwann cells and macrophages through VEGF-C signaling should alleviate inflammation and inhibit disease progression. To test these hypotheses, we propose the following Specific Aims: 1. Determine the Schwann cell-driven mechanisms that promote hepatic lymphangiogenesis. 2. Determine Kupffer cells/macrophages-driven mechanisms that promote hepatic lymphangiogenesis. 3. Determine the role of lymphangiogenesis in the development of liver fibrosis. The proposed research will elucidate the regulation of lymphatic vessels visually and mechanistically and their functional importance in liver fibrosis/cirrhosis. Further, the potential of VEGF-C overexpression and subsequent induction of lymphangiogenesis for the prevention and treatment of liver fibrosis/cirrhosis as well as portal hypertension and ascites will be evaluated. Furthermore, this research will significantly contribute to the advancement of the study of the liver by exploring relatively underexamined areas of the hepatic lymphatic system and nervous system.

PROJECT NARRATIVE The lymphatic system is essential for tissue fluid homeostasis, immune surveillance and fat absorption among others. However, the lymphatic system has been inadequately studied in the liver and its role in liver physiology and pathophysiology is poorly understood. The goal of this proposed research is to advance our understanding of the hepatic lymphatic system.