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Prepublished online as a Blood First Edition Paper on October 10, 2002; DOI 10.1182/blood-2002-05-1329.
Submitted May 6, 2002
Accepted September 23, 2002
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
Department of Molecular Genetics, Graduate School of Medicine, Kyoto University, Kyoto, Japan
Stem Cell Biology Laboratory, Center for Developmental Biology, Riken, Kobe, Japan
Division of Gastroenterology and Hepatology, Department of Internal Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan
* Corresponding author; email: kazuy{at}kuhp.kyoto-u.ac.jp.
Vascular endothelial growth factor receptor (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 ES culture system to maintain VEGFR-3+ endothelial cells (ECs) 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 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 that of VECD-1-induced dispersion for maintenance of EC integrity.
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