Mechanoinduction of lymph vessel expansion

Authors

  • Lara Planas-Paz,

    1. Institute of Metabolic Physiology, Heinrich-Heine University, Düsseldorf, Germany
    2. Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany
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  • Boris Strilić,

    1. Institute of Metabolic Physiology, Heinrich-Heine University, Düsseldorf, Germany
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    • Present address: Department of Pharmacology, Max Planck Institute for Heart and Lung Research, W.G. Kerckhoff-Institute, 61231 Bad Nauheim, Germany
  • Axel Goedecke,

    1. Institute of Cardiovascular Physiology, Heinrich-Heine University, Düsseldorf, Germany
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  • Georg Breier,

    1. Institute of Pathology, Medical Faculty, DFG Research Center and Cluster of Excellence for Regenerative Therapies, University of Technology, Dresden, Germany
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  • Reinhard Fässler,

    1. Department of Molecular Medicine, Max Planck Institute of Biochemistry, Martinsried, Germany
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  • Eckhard Lammert

    Corresponding author
    1. Institute of Metabolic Physiology, Heinrich-Heine University, Düsseldorf, Germany
    • Corresponding author. Institute of Metabolic Physiology, Heinrich-Heine University, Düsseldorf 40225, Germany. Tel.: +49 2118114990; Fax: +49 2118113897; E-mail: lammert@uni-duesseldorf.de

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  • There is a Have you seen? (February 2012) associated with this Article.

Abstract

In the mammalian embryo, few mechanical signals have been identified to influence organ development and function. Here, we report that an increase in the volume of interstitial or extracellular fluid mechanically induces growth of an organ system, that is, the lymphatic vasculature. We first demonstrate that lymph vessel expansion in the developing mouse embryo correlates with a peak in interstitial fluid pressure and lymphatic endothelial cell (LEC) elongation. In ‘loss-of-fluid’ experiments, we then show that aspiration of interstitial fluid reduces the length of LECs, decreases tyrosine phosphorylation of vascular endothelial growth factor receptor-3 (VEGFR3), and inhibits LEC proliferation. Conversely, in ‘gain-of-fluid’ experiments, increasing the amount of interstitial fluid elongates the LECs, and increases both VEGFR3 phosphorylation and LEC proliferation. Finally, we provide genetic evidence that β1 integrins are required for the proliferative response of LECs to both fluid accumulation and cell stretching and, therefore, are necessary for lymphatic vessel expansion and fluid drainage. Thus, we propose a new and physiologically relevant mode of VEGFR3 activation, which is based on mechanotransduction and is essential for normal development and fluid homeostasis in a mammalian embryo.

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