This Article Full Text Full Text (PDF) All Versions of this Article: 100/10/1468    most recent 01.RES.0000269043.51272.6dv1 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 Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Tammela, T. Articles by Alitalo, K. Search for Related Content PubMed PubMed Citation Articles by Tammela, T. Articles by Alitalo, K. Related Collections Angiogenesis Other Vascular biology

(Circulation Research. 2007;100:1468.)
© 2007 American Heart Association, Inc.

Molecular Medicine

Distinct Architecture of Lymphatic Vessels Induced by Chimeric Vascular Endothelial Growth Factor-C/Vascular Endothelial Growth Factor Heparin-Binding Domain Fusion Proteins

Tuomas Tammela^*, Yulong He^*, Johannes Lyytikkä, Michael Jeltsch, Johanna Markkanen, Katri Pajusola, Seppo Ylä-Herttuala, Kari Alitalo

From the Molecular/Cancer Biology Laboratory and Ludwig Institute for Cancer Research (T.T., Y.H., J.L., M.J., K.P., K.A.), Biomedicum Helsinki, the Haartman Institute and Helsinki University Central Hospital, University of Helsinki; and Department of Biotechnology and Molecular Medicine (J.M., S.Y.-H.), A.I. Virtanen Institute, University of Kuopio, Finland.

Correspondence to Dr Kari Alitalo, University of Helsinki, Molecular/Cancer Biology Program, Biomedicum Helsinki, POB 23 (Haartmaninkatu 8), Helsinki 00014, Finland. E-mail Kari.Alitalo{at}helsinki.fi

Vascular endothelial growth factor (VEGF)-C and VEGF-D are composed of the receptor-binding VEGF homology domain and a carboxy-terminal silk homology domain that requires proteolytic cleavage for growth factor activation. Here, we explored whether the C-terminal heparin-binding domain of the VEGF₁₆₅ or VEGF₁₈₉ isoform also containing neuropilin-binding sequences could substitute for the silk homology domain of VEGF-C. Such VEGF-C/VEGF–heparin-binding domain chimeras were produced and shown to activate VEGF-C receptors, and, when expressed in tissues via adenovirus or adeno-associated virus vectors, stimulated lymphangiogenesis in vivo. However, both chimeras induced a distinctly different pattern of lymphatic vessels when compared with VEGF-C. Whereas VEGF-C–induced vessels were initially a dense network of small diameter vessels, the lymphatic vessels induced by the chimeric growth factors tended to form directly along tissue borders, along basement membranes that are rich in heparan sulfate. For example, in skeletal muscle, the chimeras induced formation of lumenized lymphatic vessels more efficiently than wild-type VEGF-C. We conclude that the matrix-binding domain of VEGF can target VEGF-C activity to heparin-rich basement membrane structures. These properties may prove useful for tissue engineering and attempts to regenerate lymphatic vessels in lymphedema patients.

Key Words: VEGF-C • VEGF-A • heparin-binding • lymphangiogenesis

This article has been cited by other articles:

				M. Simons Silky, Sticky Chimeras-Designer VEGFs Display Their Wares Circ. Res., May 25, 2007; 100(10): 1402 - 1404. [Full Text] [PDF]