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

• Published in: Nature communications 2012-11, Vol.3 (1), p.1208, Article 1208
• Main Authors: Orsenigo, Fabrizio, Giampietro, Costanza, Ferrari, Aldo, Corada, Monica, Galaup, Ariane, Sigismund, Sara, Ristagno, Giuseppe, Maddaluno, Luigi, Young Koh, Gou, Franco, Davide, Kurtcuoglu, Vartan, Poulikakos, Dimos, Baluk, Peter, McDonald, Donald, Grazia Lampugnani, Maria, Dejana, Elisabetta
• Format: Article
• Language: English
• Subjects: 631/80/458/1733; 631/80/79/1902; 631/80/79/2028; Amino Acid Sequence; Amino acids; Animals; Antibodies; Antibody Specificity - drug effects; Antigens; Antigens, CD - immunology; Antigens, CD - metabolism; Arteries - drug effects; Arteries - physiology; Bradykinin - pharmacology; Cadherins - immunology; Cadherins - metabolism; Capillary Permeability - drug effects; Edema; Endocytosis - drug effects; Enzyme Activation - drug effects; Hemodynamics; Hemodynamics - drug effects; Human Umbilical Vein Endothelial Cells - drug effects; Human Umbilical Vein Endothelial Cells - metabolism; Humanities and Social Sciences; Humans; Inflammation Mediators - metabolism; Kinases; Mice; Mice, Inbred C57BL; Molecular Sequence Data; multidisciplinary; Peptides; Permeability; Phosphorylation; Phosphorylation - drug effects; Physiology; Science; Science (multidisciplinary); Shear stress; src-Family Kinases - metabolism; Stress, Mechanical; Ubiquitination - drug effects; Veins & arteries; Veins - drug effects; Veins - physiology
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms2199

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. Vascular endothelial-cadherin is a junctional protein implicated in the control of vascular permeability. Orsenigo et al. find that vascular endothelial-cadherin is phosphorylated in veins but not in arteries of mice, and that this sensitizes vessels to rapid changes in permeability in response to inflammatory mediators.