This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Hainaud, P. Articles by Dupuy, E. Search for Related Content PubMed PubMed Citation Articles by Hainaud, P. Articles by Dupuy, E.

The Role of the Vascular Endothelial Growth Factor–Delta-like 4 Ligand/Notch4-Ephrin B2 Cascade in Tumor Vessel Remodeling and Endothelial Cell Functions

Institut des Vaisseaux et du Sang, INSERM U689, IFR139, Paris VII-Denis Diderot, Hôpital Lariboisière, Paris, France

Requests for reprints: Evelyne Dupuy, Institut des Vaisseaux et du Sang, INSERM U689, IFR139, Paris VII-Denis Diderot, Hôpital Lariboisière, 8 rue Guy Patin, 75475 Paris, Cedex 10, France. Phone: 33-1-45-26-21-98; Fax: 33-1-42-82-94-73; E-mail: evelyne.dupuy{at}lrb.aphp.fr.

Vascular endothelial growth factor (VEGF) and Delta-like 4 ligand (DLL4) are the only genes whose haploinsufficiency results in vascular abnormalities. Although many common pathways are up-regulated in both vascular development and tumor angiogenesis and in vascular remodeling, the role of the Delta/Notch pathway has not been clearly defined in tumor angiogenesis. In this study, we assessed the expression of DLL4, Notch4, and ephrin B2 in transgenic mice developing hepatocarcinoma characterized by a strong remodeling of the tumor sinusoids. We also investigated the role of VEGF in the expression and biological functions of these molecules on human venous endothelial cells. In transgenic livers, we showed that DLL4, active Notch4, and ephrin B2 were gradually up-regulated within the hepatocarcinoma progression and expressed on tumor sinusoidal endothelial cells. In venous endothelial cells, we showed that VEGF up-regulates DLL4 and presenilin, and increased the activation of Notch4, leading to an up-regulation of ephrin B2 with a down-regulation of Eph B4. We also showed that the activation of Notch4 is required for VEGF-induced up-regulation of ephrin B2 and the differentiation of human venous endothelial cells in vitro. Accordingly, the disruption of Notch4 signaling by pharmacologic inhibition of presenilin or addition of soluble DLL4 inhibited the effect of VEGF on human venous endothelial cell migration and differentiation. Our study strongly suggests that a coordinated activation of DDL4/Notch4 and ephrin B2 pathways downstream of VEGF plays a key role in the abnormal remodeling of tumor vessels. (Cancer Res 2006; 66(17): 8501-10)

This article has been cited by other articles:

				D. Morrow, J. P. Cullen, P. A. Cahill, and E. M. Redmond Ethanol stimulates endothelial cell angiogenic activity via a Notch- and angiopoietin-1-dependent pathway Cardiovasc Res, July 15, 2008; 79(2): 313 - 321. [Abstract] [Full Text] [PDF]

				Y. Funahashi, S. L. Hernandez, I. Das, A. Ahn, J. Huang, M. Vorontchikhina, A. Sharma, E. Kanamaru, V. Borisenko, D. M. DeSilva, et al. A Notch1 Ectodomain Construct Inhibits Endothelial Notch Signaling, Tumor Growth, and Angiogenesis Cancer Res., June 15, 2008; 68(12): 4727 - 4735. [Abstract] [Full Text] [PDF]

				N. M.S. van den Akker, V. Caolo, L. J. Wisse, P. P.W.M. Peters, R. E. Poelmann, P. Carmeliet, D. G.M. Molin, and A. C. Gittenberger-de Groot Developmental coronary maturation is disturbed by aberrant cardiac vascular endothelial growth factor expression and Notch signalling Cardiovasc Res, May 1, 2008; 78(2): 366 - 375. [Abstract] [Full Text] [PDF]

				J. Mazella, S. Liang, and L. Tseng Expression of Delta-Like Protein 4 in the Human Endometrium Endocrinology, January 1, 2008; 149(1): 15 - 19. [Abstract] [Full Text] [PDF]

				C. Roca and R. H. Adams Regulation of vascular morphogenesis by Notch signaling Genes & Dev., October 15, 2007; 21(20): 2511 - 2524. [Abstract] [Full Text] [PDF]

				J. Konishi, K. S. Kawaguchi, H. Vo, N. Haruki, A. Gonzalez, D. P. Carbone, and T. P. Dang {gamma}-Secretase Inhibitor Prevents Notch3 Activation and Reduces Proliferation in Human Lung Cancers Cancer Res., September 1, 2007; 67(17): 8051 - 8057. [Abstract] [Full Text] [PDF]

				T. Gridley Notch signaling in vascular development and physiology Development, August 1, 2007; 134(15): 2709 - 2718. [Abstract] [Full Text] [PDF]

				F. A. Kudo, A. Muto, S. P. Maloney, J. M. Pimiento, S. Bergaya, T. N. Fitzgerald, T. S. Westvik, J. C. Frattini, C. K. Breuer, C. H. Cha, et al. Venous Identity Is Lost but Arterial Identity Is Not Gained During Vein Graft Adaptation Arterioscler. Thromb. Vasc. Biol., July 1, 2007; 27(7): 1562 - 1571. [Abstract] [Full Text] [PDF]

				J. S. Scehnet, W. Jiang, S. Ram Kumar, V. Krasnoperov, A. Trindade, R. Benedito, D. Djokovic, C. Borges, E. J. Ley, A. Duarte, et al. Inhibition of Dll4-mediated signaling induces proliferation of immature vessels and results in poor tissue perfusion Blood, June 1, 2007; 109(11): 4753 - 4760. [Abstract] [Full Text] [PDF]

				K. Takeshita, M. Satoh, M. Ii, M. Silver, F. P. Limbourg, Y. Mukai, Y. Rikitake, F. Radtke, T. Gridley, D. W. Losordo, et al. Critical Role of Endothelial Notch1 Signaling in Postnatal Angiogenesis Circ. Res., January 5, 2007; 100(1): 70 - 78. [Abstract] [Full Text] [PDF]