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* INSERM EMI 02-19, Laboratoire de Développement et Vieillissement de L’Endothélium, Département Réponse Dynamique Cellulaire, Commissariat à l’Energie Atomique, Grenoble Cedex 9, France; and
INSERM U525-IFR14 C
ur Muscle et Vaisseaux, Université P.M. Curie, Faculté de Médecine Pitié-Salpêtrière, Paris, Cedex 13, France
1Correspondence: INSERM EMI 0219, Département Réponse et Dynamique Cellulaire, Laboratoire de Développement et Vieillissement de l’Endothélium, CEA Grenoble, 17, rue des Martyrs, 38054 Grenoble Cedex 9, France. E-mail: ivilgrain{at}cea.fr
Platelet-activating factor (PAF), a potent inflammatory mediator, is involved in endothelial permeability. This study was designed to characterize PAF receptor (PAF-R) expression and its specific contribution to the modifications of adherens junctions in mouse endothelial cells. We demonstrated that PAF-R was expressed in mouse endothelial cells and was functionally active in stimulating p42/p44 MAPK and phosphatidylinositol 3-kinase (PtdIns3'-kinase)/Akt activities. Treatment of cells with PAF induced a rapid time- and dose-dependent (10–7 to 10–10 M) increase in tyrosine phosphorylation of a subset of proteins ranging from 90 to 220 kDa, including the VE-cadherin, the latter effect being prevented by the tyrosine kinase inhibitors herbimycin A and bis-tyrphostin. We demonstrated that PAF promoted formation of multimeric aggregates of VE-cadherin with PtdIns3'-kinase, which was also inhibited by herbimycin and bis-tyrphostin. Finally, we show by immunostaining of endothelial cells VE-cadherin that PAF dissociated adherens junctions. The present data provide the first evidence that treatment of endothelial cells with PAF promoted activation of tyrosine kinases and the VE-cadherin tyrosine phosphorylation and PtdIns3'-kinase association, which ultimately lead to the dissociation of adherens junctions. Physical association between PtdIns3'-kinase, serving as a docking protein, and VE-cadherin may thus provide an efficient mechanism for amplification and perpetuation of PAF-induced cellular activation.—Hudry-Clergeon, H., Stengel, D., Ninio, E., Vilgrain, I. Platelet-activating factor increases VE-cadherin tyrosine phosphorylation in mouse endothelial cells and its association with the PtdIns3'-kinase.
Key Words: adherens junction • VE cadherin • Akt • angiogenesis
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