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

Abstract

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.

Keywords: fibrosis; lymphangiogenesis; transforming growth factor-β; vascular endothelial growth factor-C.

Figure 1

Transforming growth factor-β (TGF-β) promotes tissue lymphangiogenesis via upregulating vascular endothelial growth factor (VEGF)-C in various fibrotic pathologies (kidney fibrosis, peritoneal fibrosis, tissue inflammation, and tumor microenvironment). Lymphangiogenesis is generally observed during tissue fibrosis. One possible mechanism is acknowledged to be the TGF-β–VEGF-C pathway. TGF-β, as a key player in tissue fibrosis, is demonstrated to have a direct inhibitory effect on the proliferation and migration of lymphatic endothelial cells (LECs) [12]. However, TGF-β is found to enhance VEGF-C production in renal proximal tubule cells [8,9], collecting tubule cells [8], peritoneal mesothelial cells [10], macrophages [8,9,10], and some tumor cells [15]. The upregulated VEGF-C increases the growth and tube formation of LECs, abrogating the inhibitory effects of TGF-β and leading to lymphangiogenesis. Additionally, connective tissue growth factor (CTGF), as induced by TGF-β in multiple kinds of cells, also promotes the production of VEGF-C during renal fibrosis [16]. Full-length CTGF binds to VEGF-C and suppresses the tube formation of LECs while the effect is counteracted by the cleavage of CTGF in vivo [16]. In summary, increased TGF-β levels promote VEGF-C production in specific cells and lead to lymphangiogenesis during tissue fibrosis.

Figure 2

Lymphangiogenesis occurs in renal and peritoneal fibrosis. Lymphangiogenesis was observed in a human diabetic nephropathy case and in a rat diaphragmatic fibrosis model induced by chlorhexidine gluconate (CG) by immunohistochemistry. D2-40 and lymphatic vessel endothelial hyaluronan receptor-1 (LYVE-1) are lymphatic markers. Arrowheads indicate lymphatic vessels. Scale bars = 100 μm.