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Prepublished online as a Blood First Edition Paper on October 10, 2002; DOI 10.1182/blood-2002-05-1329. This Article Full Text Full Text (PDF) All Versions of this Article: 2002-05-1329v1 101/4/1367    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map 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 Matsumura, K. Articles by Nishikawa, S.-I. Search for Related Content PubMed PubMed Citation Articles by Matsumura, K. Articles by Nishikawa, S.-I. Related Collections Hemostasis, Thrombosis, and Vascular Biology Signal Transduction Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  Blood, 15 February 2003, Vol. 101, No. 4, pp. 1367-1374 HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY Modulation of VEGFR-2-mediated endothelial-cell activity by VEGF-C/VEGFR-3 Kazuyoshi Matsumura, Masanori Hirashima, Minetaro Ogawa, Hajime Kubo, Hiroshi Hisatsune, Nobuyuki Kondo, Satomi Nishikawa, Tsutomu Chiba, and Shin-Ichi Nishikawa From the Division of Gastroenterology and Hepatology, Department of Internal Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan; the Department of Molecular Genetics, Graduate School of Medicine, Kyoto University, Kyoto, Japan; and the Stem Cell Biology Laboratory, Center for Developmental Biology, Kobe, Japan. Vascular endothelial growth factor (VEGF) receptor 3 (VEGFR-3), a receptor for VEGF-C, was shown to be essential for angiogenesis as well as for lymphangiogenesis. Targeted disruption of the VEGFR-3 gene in mice and our previous study using an antagonistic monoclonal antibody (MoAb) for VEGFR-3 suggested that VEGF-C/VEGFR-3 signals might be involved in the maintenance of vascular integrity. In this study we used an in vitro embryonic stem (ES) cell culture system to maintain the VEGFR-3+ endothelial cell (EC) and investigated the role of VEGFR-3 signals at the cellular level. In this system packed clusters of ECs were formed. Whereas addition of exogenous VEGF-A induced EC dispersion, VEGF-C, which can also stimulate VEGFR-2, promoted EC growth without disturbing the EC clusters. Moreover, addition of AFL4, an antagonistic MoAb for VEGFR-3, resulted in EC dispersion. Cytological analysis showed that VEGF-A- and AFL4-treated ECs were indistinguishable in many aspects but were distinct from the cytological profile induced by antagonistic MoAb for VE-cadherin (VECD-1). As AFL4- induced EC dispersion requires VEGF-A stimulation, it is likely that VEGFR-3 signals negatively modulate VEGFR-2. This result provides new insights into the involvement of VEGFR-3 signals in the maintenance of vascular integrity through modulation of VEGFR-2 signals. Moreover, our findings suggest that the mechanisms underlying AFL4-induced EC dispersion are distinct from those underlying VECD-1-induced dispersion for maintenance of EC integrity. © 2003 by The American Society of Hematology.   CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: T. Kono, H. Kubo, C. Shimazu, Y. Ueda, M. Takahashi, K. Yanagi, N. Fujita, T. Tsuruo, H. Wada, and J. K. 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