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Ephrin-B2 regulates VEGFR2 function in developmental and tumour angiogenesis

机译：Ephrin-B2调节VEGFR2在发育和肿瘤血管生成中的功能

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摘要

The formation and guidance of specialized endothelial tip cells is essential for both developmental and pathological angiogenesis. Notch-1 signalling regulates the generation of tip cells, which respond to gradients of vascular endothelial growth factor (VEGF-A). The molecular cues and signalling pathways that control the guidance of tip cells are poorly understood. Bidirectional signalling by Eph receptors and ephrin ligands represents one of the most important guidance cues involved in axon path finding. Here we show that ephrin-B2 reverse signalling involving PDZ interactions regulates endothelial tip cell guidance to control angiogenic sprouting and branching in physiological and pathological angiogenesis. In vivo, ephrin-B2 PDZ-signalling-deficient mice (ephrin-B2AV) exhibit a reduced number of tip cells with fewer filopodial extensions at the vascular front in the mouse retina. In pathological settings, impaired PDZ signalling decreases tumour vascularization and growth. Mechanistically, we show that ephrin-B2 controls VEGF receptor (VEGFR)-2 internalization and signalling. Importantly, internalization of VEGFR2 is necessary for activation and downstream signalling of the receptor and is required for VEGF-induced tip cell filopodial extension. Together, our results suggest that ephrin-B2 at the tip cell filopodia regulates the proper spatial activation of VEGFR2 endocytosis and signalling to direct filopodial extension. Blocking ephrin-B2 reverse signalling may be an attractive alternative or combinatorial anti-angiogenic therapy strategy to disrupt VEGFR2 function in tumour angiogenesis.
机译：专门的内皮尖端细胞的形成和指导对于发育和病理性血管生成都是必不可少的。 Notch-1信号传导调节提示细胞的生成，提示细胞响应血管内皮生长因子（VEGF-A）的梯度。控制尖端细胞的指导的分子线索和信号通路知之甚少。 Eph受体和ephrin配体的双向信号传导是涉及轴突路径寻找的最重要的指导线索之一。在这里，我们显示涉及PDZ相互作用的ephrin-B2反向信号调节内皮尖端细胞的指导，以控制在生理和病理性血管生成中的血管新生和分支。在体内，ephrin-B2 PDZ信号不足的小鼠（ephrin-B2AV）的尖端细胞数量减少，而在小鼠视网膜的血管前端的丝状延伸较少。在病理环境中，受损的PDZ信号传导会降低肿瘤血管生成和生长。从机理上讲，我们表明ephrin-B2控制着VEGF受体（VEGFR）-2的内在化和信号传导。重要的是，VEGFR2的内在化对于受体的激活和下游信号传导是必需的，并且对于VEGF诱导的尖端细胞丝状扩展是必需的。在一起，我们的结果表明，在尖端细胞丝状伪足处的ephrin-B2调节了VEGFR2内吞作用的适当空间激活，并指示直接丝状扩张。阻断ephrin-B2反向信号传导可能是破坏肿瘤血管生成中VEGFR2功能的有吸引力的替代方法或组合性抗血管生成治疗策略。

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  • 来源
    《Nature》 |2010年第7297期|p.487-491|共5页
  • 作者

    Suphansa Sawamiphak; Sascha Seidel; Clara L. Essmann; George A. Wilkinson; Mara E. Pitulescu; Till Acker; Amparo Acker-Palmer;

  • 作者单位

    Frankfurt Institute for Molecular Life Sciences and Institute of Cell Biology and Neuroscience, Goethe University Frankfurt, Max-von-Laue-Strasse 9, D-60438 Frankfurt am Main, Germany;

    Institute of Neuropathology, Giessen University, Arndtstrasse 16, D-35392 Giessen, Germany;

    Frankfurt Institute for Molecular Life Sciences and Institute of Cell Biology and Neuroscience, Goethe University Frankfurt, Max-von-Laue-Strasse 9, D-60438 Frankfurt am Main, Germany;

    Developmental Vascular Biology Program, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, Wisconsin 53226, USA;

    Department of Tissue Morphogenesis, Max-Planck-Institute for Molecular Biomedicine, and Faculty of Medicine, University of Muenster, Roentgenstrasse 20, D-48149 Muenster, Germany;

    Institute of Neuropathology, Giessen University, Arndtstrasse 16, D-35392 Giessen, Germany;

    Frankfurt Institute for Molecular Life Sciences and Institute of Cell Biology and Neuroscience, Goethe University Frankfurt, Max-von-Laue-Strasse 9, D-60438 Frankfurt am Main, 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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