Journal Article

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

Sun, Ting, Katsuno, Takayuki, Ito, Yasuhiko, Takei, Yoshifumi, Kinashi, Hiroshi

2018

Overview

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-β (TGF-β) is a key player in tissue fibrosis. TGF-β induces peritoneal fibrosis in association with peritoneal dialysis, and also induces peritoneal neoangiogenesis through interaction with VEGF-A. On the other hand, TGF-β has a direct inhibitory effect on lymphatic endothelial cell growth. We proposed a possible mechanism of the TGF-β⁻VEGF-C pathway in which TGF-β 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-β signaling. Further clarification of the mechanism might lead to the development of new therapeutic strategies to treat fibrotic diseases.

• Publisher: MDPI AG,MDPI
• Subject: Animals / Blood vessels / Capillaries / Connective tissue growth factor / Connective Tissue Growth Factor - genetics / Connective Tissue Growth Factor - metabolism / Connective tissues / Cytokines / Diabetes / Endothelial cells / Epithelial cells / Epithelial Cells - metabolism / Epithelial Cells - pathology / Etiology / Fibroblasts / Fibrosis / Gene Expression Regulation / Growth factors / Homeostasis / Humans / Inflammation / Kidney diseases / lymphangiogenesis / Lymphangiogenesis - genetics / Lymphatic system / Lymphatic Vessels - metabolism / Lymphatic Vessels - pathology / Macrophages / Macrophages - metabolism / Macrophages - pathology / Mitochondrial DNA / Nephrogenic Fibrosing Dermopathy - genetics / Nephrogenic Fibrosing Dermopathy - metabolism / Nephrogenic Fibrosing Dermopathy - pathology / Nephrology / Peritoneal dialysis / Peritoneal Fibrosis - genetics / Peritoneal Fibrosis - metabolism / Peritoneal Fibrosis - pathology / Peritoneum / Permeability / Proteins / Renal Insufficiency, Chronic - genetics / Renal Insufficiency, Chronic - metabolism / Renal Insufficiency, Chronic - pathology / Review / Signal Transduction / Signaling / Transforming Growth Factor beta - genetics / Transforming Growth Factor beta - metabolism / Transforming growth factor-a / Transforming growth factor-b / transforming growth factor-β / Vascular endothelial growth factor / Vascular Endothelial Growth Factor C - genetics / Vascular Endothelial Growth Factor C - metabolism / Vascular Endothelial Growth Factor D - genetics / Vascular Endothelial Growth Factor D - metabolism / Vascular Endothelial Growth Factor Receptor-3 - genetics / Vascular Endothelial Growth Factor Receptor-3 - metabolism / Vascular endothelial growth factor receptors / vascular endothelial growth factor-C