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Blood, 5 March 2009, Vol. 113, No. 10, pp. 2363-2369. Prepublished online as a Blood First Edition Paper on October 30, 2008; DOI 10.1182/blood-2008-08-172742. This Article Full Text (PDF) All Versions of this Article: blood-2008-08-172742v1 113/10/2363    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 Ito, T.-K. Articles by Ochiai, A. Search for Related Content PubMed PubMed Citation Articles by Ito, T.-K. Articles by Ochiai, A. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted August 7, 2008 Accepted October 17, 2008 Degradation of soluble VEGF receptor-1 by MMP-7 allows VEGF access to endothelial cells Ta-Kashi Ito, Genichiro Ishii, Seiji Saito, Keiichi Yano, Ayuko Hoshino, Tasuku Suzuki, and Atsushi Ochiai* Laboratory of Cancer Biology, Department of Integrated Biosciences, Graduate School of Frontier Sciences, The University of Tokyo, Kashiwa, Japan Pathology Division, Research Center for Innovative Oncology, National Cancer Center Hospital East, Kashiwa, Chiba, Japan Department of Antibody Research, Pharmaceutical Research Center, Kyowa Hakko Kogyo, Tokyo, Japan * Corresponding author; email: aochiai{at}east.ncc.go.jp. Vascular endothelial growth factor (VEGF) signaling in endothelial cells serves a critical role in physiological and pathological angiogenesis. Endothelial cells secrete soluble VEGF receptor-1 (sVEGFR-1/sFlt-1), an endogenous VEGF inhibitor that sequesters VEGF and blocks its access to VEGF receptors. This raises the question of how VEGF passes through this endogenous VEGF trap to reach its membrane receptors on endothelial cells, a step required for VEGF-driven angiogenesis. Here we show that matrix metalloproteinase-7 (MMP-7) degrades human sVEGFR-1, which increases VEGF bioavailability around the endothelial cells. Using a tube formation assay, migration assay, and coimmunoprecipitation assay with human umbilical vein endothelial cells (HUVECs), we show that the degradation of sVEGFR-1 by MMP-7 liberates the VEGF165 isoform from sVEGFR-1. The presence of MMP-7 abrogates the inhibitory effect of sVEGFR-1 on VEGF-induced phosphorylation of VEGF receptor-2 on HUVECs. These data suggest that VEGF escapes the sequestration by endothelial sVEGFR-1 and promotes angiogenesis in the presence of MMP-7. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: The ins and outs of VEGF signaling Stephen C. Ekker and Victoria M. Bedell Blood 2009 113: 2123-2124. [Full Text] [PDF] This article has been cited by other articles: Y.-L. Huang, H.-S. Lin, S.-U. Chen, and H. Lee Tyrosine Sulphation of Sphingosine 1-Phosphate 1 (S1P1) is Required for S1P-mediated Cell Migration in Primary Cultures of Human Umbilical Vein Endothelial Cells J. Biochem., December 1, 2009; 146(6): 815 - 820. [Abstract] [Full Text] [PDF] E. Bruegmann, R. Gruemmer, J. Neulen, and K. Motejlek Regulation of soluble vascular endothelial growth factor receptor 1 secretion from human endothelial cells by tissue inhibitor of metalloproteinase 1 Mol. Hum. Reprod., November 1, 2009; 15(11): 749 - 756. [Abstract] [Full Text] [PDF] S. C. Ekker and V. M. Bedell The ins and outs of VEGF signaling Blood, March 5, 2009; 113(10): 2123 - 2124. [Full Text] [PDF]

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