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Phosphorylation of VE-cadherin is modulated by haemodynamic forces and contributes to the regulation of vascular permeability in vivo

Author

Listed:
  • Fabrizio Orsenigo

    (FIRC Institute of Molecular Oncology)

  • Costanza Giampietro

    (FIRC Institute of Molecular Oncology)

  • Aldo Ferrari

    (ETH Zurich)

  • Monica Corada

    (FIRC Institute of Molecular Oncology)

  • Ariane Galaup

    (INSERM, College de France)

  • Sara Sigismund

    (FIRC Institute of Molecular Oncology)

  • Giuseppe Ristagno

    (Mario Negri Institute for Pharmacological Research)

  • Luigi Maddaluno

    (FIRC Institute of Molecular Oncology)

  • Gou Young Koh

    (Korea Advanced Institute of Science and Technology)

  • Davide Franco

    (ETH Zurich)

  • Vartan Kurtcuoglu

    (ETH Zurich
    The Interface Group, Institute of Physiology, University of Zurich)

  • Dimos Poulikakos

    (ETH Zurich)

  • Peter Baluk

    (Comprehensive Cancer Center, Cardiovascular Research Institute, University of California)

  • Donald McDonald

    (Comprehensive Cancer Center, Cardiovascular Research Institute, University of California)

  • Maria Grazia Lampugnani

    (Mario Negri Institute for Pharmacological Research)

  • Elisabetta Dejana

    (FIRC Institute of Molecular Oncology
    University of Milan, School of Sciences)

Abstract

Endothelial adherens junctions maintain vascular integrity. Arteries and veins differ in their permeability but whether organization and strength of their adherens junctions vary has not been demonstrated in vivo. Here we report that vascular endothelial cadherin, an endothelial specific adhesion protein located at adherens junctions, is phosphorylated in Y658 and Y685 in vivo in veins but not in arteries under resting conditions. This difference is due to shear stress-induced junctional Src activation in veins. Phosphorylated vascular endothelial-cadherin is internalized and ubiquitinated in response to permeability-increasing agents such as bradykinin and histamine. Inhibition of Src blocks vascular endothelial cadherin phosphorylation and bradykinin-induced permeability. Point mutation of Y658F and Y685F prevents vascular endothelial cadherin internalization, ubiquitination and an increase in permeability by bradykinin in vitro. Thus, phosphorylation of vascular endothelial cadherin contributes to a dynamic state of adherens junctions, but is not sufficient to increase vascular permeability in the absence of inflammatory agents.

Suggested Citation

  • Fabrizio Orsenigo & Costanza Giampietro & Aldo Ferrari & Monica Corada & Ariane Galaup & Sara Sigismund & Giuseppe Ristagno & Luigi Maddaluno & Gou Young Koh & Davide Franco & Vartan Kurtcuoglu & Dimo, 2012. "Phosphorylation of VE-cadherin is modulated by haemodynamic forces and contributes to the regulation of vascular permeability in vivo," Nature Communications, Nature, vol. 3(1), pages 1-15, January.
  • Handle: RePEc:nat:natcom:v:3:y:2012:i:1:d:10.1038_ncomms2199
    DOI: 10.1038/ncomms2199
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    Cited by:

    1. Chinnaswamy Tiruppathi & Dong-Mei Wang & Mohammad Owais Ansari & Shabana Bano & Yoshikazu Tsukasaki & Amitabha Mukhopadhyay & Jagdish C. Joshi & Christian Loch & Hans W. M. Niessen & Asrar B. Malik, 2023. "Ubiquitin ligase CHFR mediated degradation of VE-cadherin through ubiquitylation disrupts endothelial adherens junctions," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    2. Claire Leclech & David Gonzalez-Rodriguez & Aurélien Villedieu & Thévy Lok & Anne-Marie Déplanche & Abdul I. Barakat, 2022. "Topography-induced large-scale antiparallel collective migration in vascular endothelium," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
    3. Gopal Chovatiya & Kefei Nina Li & Jonathan Li & Sangeeta Ghuwalewala & Tudorita Tumbar, 2023. "Alk1 acts in non-endothelial VE-cadherin+ perineurial cells to maintain nerve branching during hair homeostasis," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    4. Chun-Shui Pan & Ying-Hua Liu & Yu-Ying Liu & Yu Zhang & Ke He & Xiao-Yuan Yang & Bai-He Hu & Xin Chang & Ming-Xia Wang & Xiao-Hong Wei & Jing-Yu Fan & Xin-Min Wu & Jing-Yan Han, 2015. "Salvianolic Acid B Ameliorates Lipopolysaccharide-Induced Albumin Leakage from Rat Mesenteric Venules through Src-Regulated Transcelluar Pathway and Paracellular Pathway," PLOS ONE, Public Library of Science, vol. 10(5), pages 1-14, May.
    5. Noemi Gioelli & Lisa J. Neilson & Na Wei & Giulia Villari & Wenqian Chen & Bernhard Kuhle & Manuel Ehling & Federica Maione & Sander Willox & Serena Brundu & Daniele Avanzato & Grigorios Koulouras & M, 2022. "Neuropilin 1 and its inhibitory ligand mini-tryptophanyl-tRNA synthetase inversely regulate VE-cadherin turnover and vascular permeability," Nature Communications, Nature, vol. 13(1), pages 1-16, December.

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