Ephrin-B2 controls VEGF-induced angiogenesis and lymphangiogenesis
Ephrin-B2 controls VEGF-induced angiogenesis and lymphangiogenesis
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DOI：
10.1038/nature09002
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发表时间：
2010-05-27
期刊：
影响因子：
64.8
通讯作者：
Adams, Ralf H.
中科院分区：
文献类型：
--
作者：
Wang, Yingdi;Nakayama, Masanori;Adams, Ralf H.
在发育、组织再生或某些疾病中，血管新生生长导致血管和淋巴管系统的扩张。这涉及内皮细胞的增殖和血管生成的萌发，在这一过程中，称为尖端细胞的细胞亚群获得了运动的、侵袭的行为，并延伸了丝状突起(1-3)。虽然已经认识到血管生成是由组织衍生的信号触发的，如血管内皮生长因子(VEGF)家族生长因子，但对内皮细胞中由此产生的信号过程只有部分了解。在这里，我们在小鼠和斑马鱼上进行的遗传学实验表明，EPhin-B2，一种Eph受体酪氨酸激酶的跨膜配体，促进血管新生内皮的萌发行为和运动。我们将这一促血管生成功能与ePhin-B2在血管内皮生长因子信号通路中的关键作用联系起来，我们对血管内皮生长因子受体VEGFR3进行了详细的研究。在缺乏ewitin-B2的情况下，VEGFR3在培养细胞和突变小鼠中的内化存在缺陷，这影响了小GTP酶rac1、Akt和丝裂原激活的蛋白激酶Erk的下游信号转导。我们的结果表明，完整的VEGFR3信号与受体内化相耦合。肾上腺素B2是这一过程的关键调节因子，从而控制血管生成和淋巴管生成的生长。
In development, tissue regeneration or certain diseases, angiogenic growth leads to the expansion of blood vessels and the lymphatic vasculature. This involves endothelial cell proliferation as well as angiogenic sprouting, in which a subset of cells, termed tip cells, acquires motile, invasive behaviour and extends filopodial protrusions(1-3). Although it is already appreciated that angiogenesis is triggered by tissue-derived signals, such as vascular endothelial growth factor (VEGF) family growth factors, the resulting signalling processes in endothelial cells are only partly understood. Here we show with genetic experiments in mouse and zebrafish that ephrin-B2, a transmembrane ligand for Eph receptor tyrosine kinases, promotes sprouting behaviour and motility in the angiogenic endothelium. We link this pro-angiogenic function to a crucial role of ephrin-B2 in the VEGF signalling pathway, which we have studied in detail for VEGFR3, the receptor for VEGF-C. In the absence of ephrin-B2, the internalization of VEGFR3 in cultured cells and mutant mice is defective, which compromises downstream signal transduction by the small GTPase Rac1, Akt and the mitogen-activated protein kinase Erk. Our results show that full VEGFR3 signalling is coupled to receptor internalization. Ephrin-B2 is a key regulator of this process and thereby controls angiogenic and lymphangiogenic growth.