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Ephrin-B2 controls VEGF-induced angiogenesis and lymphangiogenesis

机译：Ephrin-B2控制VEGF诱导的血管生成和淋巴管生成

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摘要

In development, tissue regeneration or certain diseases, angio-genic 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 filopo-dial protrusions. Although it is already appreciated that angio-genesis 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.
机译：在发育，组织再生或某些疾病中，血管源性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以及血管新生，其中一部分细胞（称为尖端细胞）获得活动性，侵袭性行为并延伸丝状突突。尽管已经认识到血管生成是由组织来源的信号触发的，例如血管内皮生长因子（VEGF）家族生长因子，但是内皮细胞中产生的信号传导过程只是部分被理解。在这里，我们通过小鼠和斑马鱼的遗传实验表明，ephrin-B2是Eph受体酪氨酸激酶的跨膜配体，可促进血管生成内皮的发芽行为和运动。我们将此促血管生成功能与ephrin-B2在VEGF信号通路中的关键作用联系起来，我们已经对VEGF-C的受体VEGFR3进行了详细研究。在缺乏麻黄素B2的情况下，在培养的细胞和突变小鼠中VEGFR3的内在化是有缺陷的，这会损害小GTPase Rac1，Akt和促分裂原活化蛋白激酶Erk的下游信号转导。我们的结果表明，完整的VEGFR3信号传导与受体内化有关。 Ephrin-B2是该过程的关键调节剂，因此可控制血管生成和淋巴血管生成的生长。

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  • 来源
    《Nature》 |2010年第7297期|p.483-486|共4页
  • 作者

    Yingdi Wang; Masanori Nakayama; Mara E. Pitulescu; Tim S. Schmidt; Magdalena L. Bochenek; Akira Sakakibara; Susanne Adams; Alice Davy; Urban Deutsch; Urs Luethi; Alcide Barberis; Laura E. Benjamin; Taija Maekinen; Catherine D. Nobes; Ralf H. Adams;

  • 作者单位

    Vascular Development Laboratory, Cancer Research UK London Research Institute, London WC2A 3PX, UK;

    Department of Tissue Morphogenesis, Max-Planck-Institute for Molecular Biomedicine, and Faculty of Medicine, University of Muenster, D-48149 Muenster, Germany;

    Department of Tissue Morphogenesis, Max-Planck-Institute for Molecular Biomedicine, and Faculty of Medicine, University of Muenster, D-48149 Muenster, Germany;

    Vascular Development Laboratory, Cancer Research UK London Research Institute, London WC2A 3PX, UK;

    Department of Tissue Morphogenesis, Max-Planck-Institute for Molecular Biomedicine, and Faculty of Medicine, University of Muenster, D-48149 Muenster, Germany Departments of Physiology & Pharmacology and Biochemistry, School of Medical Sciences, University of Bristol, Bristol BS6 6BS, UK;

    Vascular Development Laboratory, Cancer Research UK London Research Institute, London WC2A 3PX, UK;

    Vascular Development Laboratory, Cancer Research UK London Research Institute, London WC2A 3PX, UK Department of Tissue Morphogenesis, Max-Planck-Institute for Molecular Biomedicine, and Faculty of Medicine, University of Muenster, D-48149 Muenster, Germany;

    Centre de Biologie du Developpement, Universite de Toulouse, CNRS, CBD UMR 5547, F-31062 Toulouse cedex 9, France;

    Theodor Kocher Institute, University of Berne, CH-3012 Bern, Switzerland;

    Oncalis AG, Schlieren, Switzerland;

    Oncalis AG, Schlieren, Switzerland;

    Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215-5501, USA;

    Cancer Research UK London Research Institute, Lymphatic Development Laboratory, London WC2A 3PX, UK;

    Departments of Physiology & Pharmacology and Biochemistry, School of Medical Sciences, University of Bristol, Bristol BS6 6BS, UK;

    Vascular Development Laboratory, Cancer Research UK London Research Institute, London WC2A 3PX, UK Department of Tissue Morphogenesis, Max-Planck-Institute for Molecular Biomedicine, and Faculty of Medicine, University of Muenster, D-48149 Muenster, Germany;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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