S-nitrosylation of beta-catenin by eNOS-derived NO promotes VEGF-induced endothelial cell permeability.
Disruption of adherens junctions between endothelial cells results in compromised endothelial barrier function and in altered angiogenesis. Nitric oxide (NO) produced by endothelial NO synthase (eNOS) is essential for increased vascular permeability induced by vascular endothelial growth factor (VEGF). However, the molecular mechanisms by which NO modulates endothelial permeability remain elusive. Here, we show that, within adherens junctions, beta-catenin is a substrate for S-nitrosylation by NO. Stimulation of endothelial cells with VEGF induces S-nitrosylation of beta-catenin, which is dependent on expression and activity of eNOS. Furthermore, VEGF-induced S-nitrosylation of beta-catenin is inhibited in eNOS(-/-) mice. We identify Cys619, located within the VE-cadherin interaction site, as the major S-nitrosylation locus in response to VEGF. Inhibition of S-nitrosylation at Cys619 prevents NO-dependent dissociation of beta-catenin from VE-cadherin and disassembly of adherens junction complexes and inhibits VEGF-stimulated endothelial permeability. Thus, we identify S-nitrosylation of beta-catenin as a modulator of intercellular contacts between endothelial cells.
Thibeault
Sébastien
S
Laboratory of Endothelial Cell Biology, Institut de recherches cliniques de Montréal (IRCM), Université de Montréal, Montreal, Quebec, Canada.
Rautureau
Yohann
Y
Oubaha
Malika
M
Faubert
Denis
D
Wilkes
Brian C
BC
Delisle
Chantal
C
Gratton
Jean-Philippe
JP
D022005:Adherens Junctions / Q000235:genetics / Q000378:metabolism; D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D002199:Capillary Permeability / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D003545:Cysteine / Q000235:genetics / Q000378:metabolism; D042783:Endothelial Cells / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000235:genetics / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III / Q000235:genetics / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism* / Q000494:pharmacology; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*; D000099152:Cadherin 5
D015703:Antigens, CD; D015820:Cadherins; D003545:Cysteine; D009569:Nitric Oxide; D052250:Nitric Oxide Synthase Type III; D042461:Vascular Endothelial Growth Factor A; D051176:beta Catenin; D000099152:Cadherin 5; C467480:vascular endothelial growth factor A, mouse; C496315:Nos3 protein, mouse