Published online before print September 18, 2003, doi: 10.1161/01.ATV.0000096655.56262.56
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© 2003 American Heart Association, Inc.
Vascular Biology |
Ephrin-B2 Induces Migration of Endothelial Cells Through the Phosphatidylinositol-3 Kinase Pathway and Promotes Angiogenesis in Adult Vasculature
From the Department of Cell Differentiation (H.M., Y.O., Y.I., Y.Y., T.S.), The Sakaguchi Laboratory, School of Medicine, Keio University, Tokyo; Department of Cardiovascular Medicine (H.M., R.N.), Graduate School of Medicine, The University of Tokyo, Tokyo; Department of Molecular Microbiology and Immunology (S.K.), Division of Endothelial Cell Biology, Nagasaki University Graduate School of Medicine, Nagasaki; and Department of Embryogenesis (H.M., H.K.) Division of Integrative Cell Biology, Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto, Japan.
Correspondence to Toshio Suda, MD, PhD, Department of Cell Differentiation, The Sakaguchi Laboratory, School of Medicine, Keio University, 35 Shinano-machi, Shinjyuku-ku, Tokyo 160-8582, Japan. E-mail sudato{at}sc.itc.keio.ac.jp
Objective— Ephrin-B2 plays a key role in vascular development. The purpose of this study was to elucidate the molecular mechanisms of ephrin-B2 signaling through the EphB receptor in endothelial cells and to determine whether ephrin-B2 contributes to in vivo angiogenesis in adult mice.
Methods and Results— A chemotaxis assay on a polycarbonate membrane revealed that ephrin-B2/Fc chimeric protein induced migration of human umbilical vein endothelial cells (HUVECs) at a level 98% greater than control (P<0.01). To determine the signaling pathways activated in the HUVECs by Eph stimulation, phosphatidylinositol-3 kinase (PI3 kinase) activity was determined in an immune complex PI3 kinase assay. Serum-starved HUVECs were stimulated with ephrin-B2/Fc and compared with unstimulated cells. PI3 kinase activity in stimulated cells was higher than that seen in unstimulated cells. In a chemotaxis assay, the PI3 kinase-specific inhibitor LY294002 blocked the migratory response of HUVECs induced by addition of ephrin-B2/Fc. Finally, ephrin-B2/Fc promoted angiogenesis in vivo in corneal neovascularization and Matrigel plug assays in adult mice, whereas LY294002 reduced angiogenesis in Matrigel that was induced by ephrin-B2/Fc.
Conclusions— Ephrin-B2/Fc induces the migration of HUVECs through the PI3 kinase signaling pathway. Ephrin-B2/Fc promotes in vivo angiogenesis in adult mice, suggesting that it contributes to adult angiogenesis.
Key Words: ephrin-B2 • angiogenesis • phosphatidylinositol-3 kinase • migration • endothelial cells
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