Published online before print January 20, 2005, doi: 10.1161/01.RES.0000156652.99586.9f
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Submitted on September 21, 2004
Revised on January 10, 2005
Accepted on January 10, 2005
Vascular Endothelial-Cadherin Tyrosine Phosphorylation in Angiogenic and Quiescent Adult Tissues
Nathalie Lambeng ;
From INSERM, CEA (N.L., Y.W., C.R., F.C., G.C., I.V., P.H.), Université J. Fourier EMI 02-19, Laboratoire de Développement et Vieillissement de l’Endothélium, Grenoble; and Laboratoire d’Ingénierie des Macromolécules (D.G.-D.), Institut de Biologie Structurale Jean-Pierre Ebel, CNRS, CEA, Université J, Grenoble, France.
* To whom correspondence should be addressed. E-mail: ivilgrain{at}cea.fr.
Vascular endothelial-cadherin (VE-cadherin) plays a key role in angiogenesis and in vascular permeability. The regulation of its biological activity may be a central mechanism in normal or pathological angiogenesis. VE-cadherin has been shown to be phosphorylated on tyrosine in vitro under various conditions, including stimulation by VEGF. In the present study, we addressed the question of the existence of a tyrosine phosphorylated form of VE-cadherin in vivo, in correlation with the quiescent versus angiogenic state of adult tissues. Phosphorylated VE-cadherin was detected in mouse lung, uterus, and ovary but not in other tissues unless mice were injected with peroxovanadate to block protein phosphatases. Remarkably, VE-cadherin tyrosine phosphorylation was dramatically increased in uterus and ovary, and not in other organs, during PMSG/hCG-induced angiogenesis. In parallel, we observed an increased association of VE-cadherin with Flk1 (VEGF receptor 2) during hormonal angiogenesis. Additionally, Src kinase was constitutively associated with VE-cadherin in both quiescent and angiogenic tissues and increased phosphorylation of VE-cadherin-associated Src was detected in uterus and ovary after hormonal treatment. Src-VE-cadherin association was detected in cultured endothelial cells, independent of VE-cadherin phosphorylation state and Src activation level. In this model, Src inhibition impaired VEGF-induced VE-cadherin phosphorylation, indicating that VE-cadherin phosphorylation was dependent on Src activation. We conclude that VE-cadherin is a substrate for tyrosine kinases in vivo and that its phosphorylation, together with that of associated Src, is increased by angiogenic stimulation. Physical association between Flk1, Src, and VE-cadherin may thus provide an efficient mechanism for amplification and perpetuation of VEGF-stimulated angiogenic processes.
Key words: VE-cadherin • tyrosine kinase • endothelium • angiogenesis
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