Vascular Endothelial–Cadherin Tyrosine Phosphorylation in Angiogenic and Quiescent Adult Tissues

• Published in: Circulation research 2005-02, Vol.96 (3), p.384-391
• Main Authors: Lambeng, Nathalie, Wallez, Yann, Rampon, Christine, Cand, Francine, Christé, Georges, Gulino-Debrac, Danielle, Vilgrain, Isabelle, Huber, Philippe
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Cadherins - chemistry; Cadherins - metabolism; Cell Extracts - chemistry; Cell Line; Endothelial Cells - chemistry; Endothelial Cells - metabolism; Endothelium, Vascular - chemistry; Endothelium, Vascular - cytology; Endothelium, Vascular - metabolism; Female; Fundamental and applied biological sciences. Psychology; Gonadotropins, Equine - pharmacology; Humans; Mice; Mice, Inbred C57BL; Neovascularization, Physiologic - physiology; Ovary - drug effects; Ovary - metabolism; Phosphorylation - drug effects; Phosphotyrosine - metabolism; Proteins - chemistry; Proteins - metabolism; Proto-Oncogene Proteins pp60(c-src) - antagonists & inhibitors; Proto-Oncogene Proteins pp60(c-src) - metabolism; Umbilical Veins - cytology; Uterus - drug effects; Uterus - metabolism; Vanadates - administration & dosage; Vanadates - pharmacology; Vascular Endothelial Growth Factor Receptor-2 - metabolism; Vertebrates: cardiovascular system
• ISSN: 0009-7330; 1524-4571
• DOI: 10.1161/01.RES.0000156652.99586.9f

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.