Key Laboratory of Protein and Peptide Pharmaceuticals, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China.
College of Life Sciences, University of Chinese Academy of Sciences, Beijing, 100049, China.
Sci Rep. 2017 Aug 7;7(1):7442. doi: 10.1038/s41598-017-06637-7.
VEGF-C is essential for lymphangiogenesis during development and tumor progression. VEGFR-3 is the well-known cognate receptor of VEGF-C to regulate lymphatic migration and proliferation, but the receptor of VEGF-C in regulating lymphatic sprouting, the initiating step of lymphangiogenesis, still remains elusive. Here we use both in vitro and in vivo methods to demonstrate CD146 as a receptor of VEGF-C to regulate lymphangiogenesis, especially at the sprouting step. Mechanistically, CD146 selectively activates the downstream p38 kinase, upon VEGF-C stimulation, to regulate lymphatic sprouting. Moreover, CD146 can also activate ERK to mediate VEGF-C regulation of the subsequent proliferation and migration of lymphatic endothelial cells. In zebrafish embryos, knockdown or dysfunction of CD146 results in similar developmental defects in lymphatic sprouting, capillary network, parachordal lymphangioblast (PL), and thoracic duct (TD) similar to down-regulation of VEGF-C. Altogether, our data reveals a critical role of CD146 to mediate VEGF-C signaling pathway in lymphangiogenesis.
VEGF-C 对于发育过程中和肿瘤进展中的淋巴管生成是必不可少的。VEGFR-3 是 VEGF-C 的众所周知的同源受体，可调节淋巴管迁移和增殖，但 VEGF-C 在调节淋巴管发芽（淋巴管生成的起始步骤）中的受体仍然难以捉摸。在这里，我们使用体外和体内方法来证明 CD146 是 VEGF-C 的受体，可调节淋巴管生成，特别是在发芽步骤。从机制上讲，CD146 在受到 VEGF-C 刺激时选择性地激活下游 p38 激酶，从而调节淋巴管发芽。此外，CD146 还可以激活 ERK 来介导 VEGF-C 对随后的淋巴管内皮细胞增殖和迁移的调节。在斑马鱼胚胎中，CD146 的敲低或功能障碍导致淋巴管发芽、毛细血管网络、parachordal lymphangioblast（PL）和胸导管（TD）的发育缺陷与 VEGF-C 的下调相似。总的来说，我们的数据揭示了 CD146 在介导 VEGF-C 信号通路在淋巴管生成中的关键作用。
