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Blood, 9 April 2009, Vol. 113, No. 15, pp. 3631-3639. Prepublished online as a Blood First Edition Paper on February 13, 2009; DOI 10.1182/blood-2008-07-170381. This Article Full Text (PDF) All Versions of this Article: blood-2008-07-170381v1 113/15/3631    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Yamanda, S. Articles by Arai, H. Search for Related Content PubMed PubMed Citation Articles by Yamanda, S. Articles by Arai, H. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted July 25, 2008 Accepted February 4, 2009 Role of ephrinB2 in non-productive angiogenesis induced by Delta-like 4 blockade Shinsuke Yamanda, Satoru Ebihara*, Masanori Asada, Tatsuma Okazaki, Kaijun Niu, Takae Ebihara, Akemi Koyanagi, Noriko Yamaguchi, Hideo Yagita, and Hiroyuki Arai Department of Geriatrics and Gerontology, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan Division of Cell Biology, Juntendo University School of Medicine, Tokyo, Japan Department of Immunology, Juntendo University School of Medicine, Tokyo, Japan * Corresponding author; email: sebihara{at}idac.tohoku.ac.jp. Delta-like 4 (DLL4) is one of the Notch ligands and plays an important role in vascular development. DLL4 blockade inhibits tumor growth by promoting non-productive angiogenesis, which is characterized by an increase in vascular density and decrease in tissue perfusion. However, a detailed mechanism remains unclear. In this study, newly developed neutralizing antibodies against mouse and human DLL4 were used to investigated the possible involvement of VEGF-DLL4-ephrinB2 cascade in non-productive angiogenesis caused by DLL4 blockade in vivo and in vitro. DLL4 blockade and soluble ephrinB2 treatment suppressed tumor growth and induced non-productive angiogenesis. DLL4 was expressed in subcutaneous tumors, and DLL4 blockade suppressed ephrinB2 expression in the tumors. DLL4 blockade significantly promoted HUVECs proliferation in vitro, and the effect was additive to that of VEGF. Both DLL4 blockade and VEGF significantly increased cord length and branch points in a tubular formation assay. Expression of ephrinB2 in HUVECs was enhanced by VEGF alone, and the enhancement was inhibited by DLL4 blockade. Moreover, when we studied the effect of ephrinB2 RNA interference on HUVECs tubular formation, knockdown of ephrinB2 mimicked the effect of DLL4. These results suggest that ephrinB2 plays a crucial role in non-productive angiogenesis caused by DLL4 blockade. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: A. Pennisi, W. Ling, X. Li, S. Khan, J. D. Shaughnessy Jr, B. Barlogie, and S. Yaccoby The ephrinB2/EphB4 axis is dysregulated in osteoprogenitors from myeloma patients and its activation affects myeloma bone disease and tumor growth Blood, August 27, 2009; 114(9): 1803 - 1812. [Abstract] [Full Text] [PDF]

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