QUICK SEARCH:   [advanced] Author: Keyword(s):
Home     Help     Feedback     Subscriptions     Archive     Search     Table of Contents

First published online 18 May 2004
doi: 10.1242/jcs.01138

This Article Figures Only Full Text Full Text (PDF) Supplemental Figure All Versions of this Article: jcs.01138v1 jcs.01138v2 117/13/2745    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 Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Persaud, K. Articles by Pytowski, B. Search for Related Content PubMed PubMed Citation Articles by Persaud, K. Articles by Pytowski, B.

Involvement of the VEGF receptor 3 in tubular morphogenesis demonstrated with a human anti-human VEGFR-3 monoclonal antibody that antagonizes receptor activation by VEGF-C

¹ ImClone Systems Incorporated, New York, NY 10014, USA
² Department of Morphology, University Medical Center, Geneva, Switzerland

^* Author for correspondence (e-mail: bronek{at}imclone.com)

Accepted 3 February 2004

In this report we utilize a novel antagonist antibody to the human VEGFR-3 to elucidate the role of this receptor in in vitro tubular morphogenesis of bovine and human endothelial cells (EC cells) induced by VEGF-C. The antibody hF4-3C5 was obtained by panning a human phage display library on soluble human VEGFR-3. The binding affinity constant of hF4-3C5 significantly exceeds that of the interaction of VEGFR-3 with VEGF-C. hF4-3C5 strongly inhibits the binding of soluble VEGFR-3 to immobilized VEGF-C and abolishes the VEGF-C-mediated mitogenic response of cells that expresses a chimeric human VEGFR-3-cFMS receptor. In fluorescence experiments, hF4-3C5 reactivity is observed with human lymphatic endothelial cells (LECs) and human umbilical vein endothelial cells (HUVECs). Binding of hF4-3C5 shows that about half of bovine aortic endothelial (BAE) cells express VEGFR-3 and cells in this subpopulation are primarily responsible for the chemotactic response to the mature form of VEGF-C (VEGF-C_NC). This response was strongly inhibited by the addition of hF4-3C5. In vitro tube formation by BAE cells induced by VEGF-C_NC was reduced by greater than 60% by hF4-3C5 whereas the response to VEGF₁₆₅ was unaffected. Addition of hF4-3C5 together with an antagonist antibody to VEGFR-2 completely abolished the response to VEGF-C_NC. Similar results were obtained with HUVECs. Together, these findings point to a role for VEGFR-3 in vascular tubular morphogenesis and highlight the utility of hF4-3C5 as a tool for the investigation of the biology of VEGFR-3.

Key words: VEGFR-3, Flt-4, VEGF-C

This article has been cited by other articles:

				J. W. Shin, R. Huggenberger, and M. Detmar Transcriptional profiling of VEGF-A and VEGF-C target genes in lymphatic endothelium reveals endothelial-specific molecule-1 as a novel mediator of lymphangiogenesis Blood, September 15, 2008; 112(6): 2318 - 2326. [Abstract] [Full Text] [PDF]

				C.R. Dass, T.M.N. Tran, and P.F.M. Choong Angiogenesis Inhibitors and the Need for Anti-angiogenic Therapeutics J. Dent. Res., October 1, 2007; 86(10): 927 - 936. [Abstract] [Full Text] [PDF]

				J. Goldman, J. M. Rutkowski, J. D. Shields, M. C. Pasquier, Y. Cui, H. G. Schmokel, S. Willey, D. J. Hicklin, B. Pytowski, and M. A. Swartz Cooperative and redundant roles of VEGFR-2 and VEGFR-3 signaling in adult lymphangiogenesis FASEB J, April 1, 2007; 21(4): 1003 - 1012. [Abstract] [Full Text] [PDF]

				P. Laakkonen, M. Waltari, T. Holopainen, T. Takahashi, B. Pytowski, P. Steiner, D. Hicklin, K. Persaud, J. R. Tonra, L. Witte, et al. Vascular Endothelial Growth Factor Receptor 3 Is Involved in Tumor Angiogenesis and Growth Cancer Res., January 15, 2007; 67(2): 593 - 599. [Abstract] [Full Text] [PDF]

				C. Wissmann and M. Detmar Pathways Targeting Tumor Lymphangiogenesis Clin. Cancer Res., December 1, 2006; 12(23): 6865 - 6868. [Abstract] [Full Text] [PDF]

				X. Zhang, J. F. Wang, B. Chandran, K. Persaud, B. Pytowski, J. Fingeroth, and J. E. Groopman Kaposi's Sarcoma-associated Herpesvirus Activation of Vascular Endothelial Growth Factor Receptor 3 Alters Endothelial Function and Enhances Infection J. Biol. Chem., July 15, 2005; 280(28): 26216 - 26224. [Abstract] [Full Text] [PDF]

				J. Smith, R. E. Kontermann, J. Embleton, and S. Kumar Antibody phage display technologies with special reference to angiogenesis FASEB J, March 1, 2005; 19(3): 331 - 341. [Abstract] [Full Text] [PDF]

				X. Jimenez, D. Lu, L. Brennan, K. Persaud, M. Liu, H. Miao, L. Witte, and Z. Zhu A recombinant, fully human, bispecific antibody neutralizes the biological activities mediated by both vascular endothelial growth factor receptors 2 and 3 Mol. Cancer Ther., March 1, 2005; 4(3): 427 - 434. [Abstract] [Full Text] [PDF]

				B. Pytowski, J. Goldman, K. Persaud, Y. Wu, L. Witte, D. J. Hicklin, M. Skobe, K. C. Boardman, and M. A. Swartz Complete and Specific Inhibition of Adult Lymphatic Regeneration by a Novel VEGFR-3 Neutralizing Antibody J Natl Cancer Inst, January 5, 2005; 97(1): 14 - 21. [Abstract] [Full Text] [PDF]

				R. E. Nisato, J. A. Harrison, R. Buser, L. Orci, C. Rinsch, R. Montesano, P. Dupraz, and M. S. Pepper Generation and Characterization of Telomerase-Transfected Human Lymphatic Endothelial Cells with an Extended Life Span Am. J. Pathol., July 1, 2004; 165(1): 11 - 24. [Abstract] [Full Text] [PDF]