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

Fabrizio Orsenigo, Costanza Giampietro, Aldo Ferrari, Monica Corada, Ariane Galaup, Sara Sigismund, Giuseppe Ristagno, Luigi Maddaluno, Gou Young Koh, Davide Franco, Vartan Kurtcuoglu, Dimos Poulikakos, Peter Baluk, Donald McDonald, Maria Grazia Lampugnani and Elisabetta Dejana ()
Additional contact information
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
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

Nature Communications, 2012, vol. 3, issue 1, 1-15

Abstract: 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.

Date: 2012
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DOI: 10.1038/ncomms2199

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