title: Mechanoinduction of lymph vessel expansion.
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.
authors.affiliation: Institute of Metabolic Physiology, Heinrich-Heine University, Düsseldorf, Germany.
authors.forename: Lara
authors.initials: L
authors.lastname: Planas-Paz
authors.forename: Boris
authors.initials: B
authors.lastname: Strilić
authors.forename: Axel
authors.initials: A
authors.lastname: Goedecke
authors.forename: Georg
authors.initials: G
authors.lastname: Breier
authors.forename: Reinhard
authors.initials: R
authors.lastname: Fässler
authors.forename: Eckhard
authors.initials: E
authors.lastname: Lammert
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D006801:Humans; D019012:Integrin beta1 / Q000235:genetics / Q000502:physiology; D042601:Lymphatic Vessels / Q000166:cytology*; D040542:Mechanotransduction, Cellular; D051379:Mice; D010766:Phosphorylation; D015398:Signal Transduction; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000378:metabolism
chemical_list: D019012:Integrin beta1; D040321:Vascular Endothelial Growth Factor Receptor-3