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

Department of Nephrology and Rheumatology, Aichi Medical University, Nagakute 480-1195, Japan
Department of Nephrology and Renal Replacement Therapy, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan
Department of Medicinal Biochemistry, School of Pharmacy, Aichi Gakuin University, Nagoya 464-8650, Japan
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2018, 19(9), 2487;
Received: 14 July 2018 / Revised: 16 August 2018 / Accepted: 18 August 2018 / Published: 23 August 2018
(This article belongs to the Special Issue TGF-Beta Super Family Signaling)
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. View Full-Text
Keywords: lymphangiogenesis; fibrosis; transforming growth factor-β; vascular endothelial growth factor-C lymphangiogenesis; fibrosis; transforming growth factor-β; vascular endothelial growth factor-C
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MDPI and ACS Style

Kinashi, H.; Ito, Y.; Sun, T.; Katsuno, T.; Takei, Y. Roles of the TGF-β–VEGF-C Pathway in Fibrosis-Related Lymphangiogenesis. Int. J. Mol. Sci. 2018, 19, 2487.

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