Roles of the TGF-β-VEGF-C Pathway in Fibrosis-Related Lymphangiogenesis

Lymphatic vessels drain excess tissue fluids to maintain the interstitial environment. Lymphatic capillaries develop during the progression of tissue fibrosis in various clinical and pathological situations, such as chronic kidney disease, peritoneal injury during peritoneal dialysis, tissue inflammation, and tumor progression. The role of fibrosis-related lymphangiogenesis appears to vary based on organ specificity and etiology. Signaling via vascular endothelial growth factor (VEGF)-C, VEGF-D, and VEGF receptor (VEGFR)-3 is a central molecular mechanism for lymphangiogenesis. Transforming growth factor-beta (TGF-beta) is a key player in tissue fibrosis. TGF-beta induces peritoneal fibrosis in association with peritoneal dialysis, and also induces peritoneal neoangiogenesis through interaction with VEGF-A. On the other hand, TGF-beta has a direct inhibitory effect on lymphatic endothelial cell growth. We proposed a possible mechanism of the TGF-beta-VEGF-C pathway in which TGF-beta promotes VEGF-C production in tubular epithelial cells, macrophages, and mesothelial cells, leading to lymphangiogenesis in renal and peritoneal fibrosis. Connective tissue growth factor (CTGF) is also involved in fibrosis-associated renal lymphangiogenesis through interaction with VEGF-C, in part by mediating TGF-beta signaling. Further clarification of the mechanism might lead to the development of new therapeutic strategies to treat fibrotic diseases.