Essential role of Apelin signaling during lymphatic development in zebrafish.
Essential role of Apelin signaling during lymphatic development in zebrafish.
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DOI：
10.1161/atvbaha.113.302785
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发表时间：
2014-02
期刊：
影响因子：
--
通讯作者：
Jin SW
中科院分区：
文献类型：
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作者：
Kim JD;Kang Y;Kim J;Papangeli I;Kang H;Wu J;Park H;Nadelmann E;Rockson SG;Chun HJ;Jin SW
Apelin及其同源受体Aplnr/Apj是多种生物过程所必需的。然而，尽管Apelin和Aplnr在脊椎动物的发育中的血液（BEC）和淋巴管内皮细胞（LEC）内优先表达，但Apelin信号传导在淋巴发育中的功能仍有待鉴定。在这份报告中，我们的目的是描绘爱帕琳信号在淋巴发育过程中的功能。我们使用斑马鱼胚胎研究了Apelin信号在淋巴发育过程中的功能，发现Apelin信号的衰减显著降低了发育中胸导管内的副索血管（PaCV）的形成和LEC的数量，表明Apelin信号在淋巴发育的早期阶段中起着重要作用。从机制上讲，我们发现Apelin信号的消除选择性地减弱淋巴管内皮细胞AKT 1/2磷酸化，而不影响ERK 1/2的磷酸化状态。此外，由Apelin信号传导减少引起的淋巴异常因同时部分抑制AKT信号传导而显着加剧。爱帕琳和血管内皮生长因子-C（VEGF-C）信号传导在淋巴发育期间提供AKT的非冗余激活，因为VEGF-C或爱帕琳的过表达不能分别挽救由爱帕琳或VEGF-C缺乏引起的淋巴缺陷。总之，我们的数据提供了令人信服的证据，表明Apelin信号通过促进斑马鱼胚胎发育过程中VEGF-C/VEGFR 3独立方式的AKT活性来调节淋巴发育。
Apelin and its cognate receptor Aplnr/Apj are essential for diverse biological processes. However, the function of Apelin signaling in lymphatic development remains to be identified, despite the preferential expression of Apelin and Aplnr within developing blood (BECs) and lymphatic endothelial cells (LECs) in vertebrates. In this report, we aim to delineate the functions of Apelin signaling during lymphatic development. We investigated the functions of Apelin signaling during lymphatic development using zebrafish embryos, and found that attenuation of Apelin signaling substantially decreased the formation of the parachordal vessel (PaCV) and the number of LECs within the developing thoracic duct, indicating an essential role of Apelin signaling during the early phase of lymphatic development. Mechanistically, we found that abrogation of Apelin signaling selectively attenuates lymphatic endothelial AKT1/2 phosphorylation without affecting the phosphorylation status of ERK1/2. Moreover, lymphatic abnormalities caused by the reduction of Apelin signaling were significantly exacerbated by the concomitant partial inhibition of AKT signaling. Apelin and Vascular Endothelial Growth Factor-C (VEGF-C) signaling provide a non-redundant activation of AKT during lymphatic development, as over-expression of VEGF-C or apelin was unable to rescue the lymphatic defects caused by the lack of Apelin or VEGF-C, respectively. Taken together, our data present compelling evidence suggesting that Apelin signaling regulates lymphatic development by promoting AKT activity in a VEGF-C/VEGFR3 independent manner during zebrafish embryogenesis.