Roles of the TGF-β⁻VEGF-C Pathway in Fibrosis-Related Lymphangiogenesis.
Roles of the TGF-β⁻VEGF-C Pathway in Fibrosis-Related Lymphangiogenesis.
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DOI：
10.3390/ijms19092487
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发表时间：
2018-08-23
影响因子：
5.6
通讯作者：
Takei Y
中科院分区：
文献类型：
--
作者：
Kinashi H;Ito Y;Sun T;Katsuno T;Takei Y
淋巴管排出多余的组织液以维持间质环境。在各种临床和病理情况下，如慢性肾脏疾病、腹膜透析时的腹膜损伤、组织炎症和肿瘤进展，在组织纤维化的进展过程中会出现淋巴毛细血管。纤维化相关淋巴管生成的作用似乎因器官特异性和病因而异。通过血管内皮生长因子(VEGF)-C、VEGF- d和VEGF受体(VEGFR)-3传递的信号是淋巴管生成的主要分子机制。转化生长因子-β (TGF-β)在组织纤维化中起关键作用。TGF-β与腹膜透析相关诱导腹膜纤维化，并通过与VEGF-A相互作用诱导腹膜新生血管生成。另一方面，TGF-β对淋巴内皮细胞生长有直接抑制作用。我们提出了TGF-β - VEGF-C通路的可能机制，其中TGF-β促进小管上皮细胞、巨噬细胞和间皮细胞中VEGF-C的产生，导致肾和腹膜纤维化的淋巴管生成。结缔组织生长因子（CTGF）也通过与VEGF-C相互作用参与纤维化相关肾淋巴管生成，部分通过介导TGF-β信号传导。进一步阐明这一机制可能有助于开发治疗纤维化疾病的新治疗策略。
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.
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