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Science 30 May 1997:
Vol. 276. no. 5317, pp. 1423 - 1425
DOI: 10.1126/science.276.5317.1423
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Reports

Hyperplasia of Lymphatic Vessels in VEGF-C Transgenic Mice

Michael Jeltsch, * Arja Kaipainen, * Vladimir Joukov, Xiaojuan Meng, Merja Lakso, Heikki Rauvala, Melody Swartz, Dai Fukumura, Rakesh K. Jain, Kari Alitalo dagger

No growth factors specific for the lymphatic vascular system have yet been described. Vascular endothelial growth factor (VEGF) regulates vascular permeability and angiogenesis, but does not promote lymphangiogenesis. Overexpression of VEGF-C, a ligand of the VEGF receptors VEGFR-3 and VEGFR-2, in the skin of transgenic mice resulted in lymphatic, but not vascular, endothelial proliferation and vessel enlargement. Thus, VEGF-C induces selective hyperplasia of the lymphatic vasculature, which is involved in the draining of interstitial fluid and in immune function, inflammation, and tumor metastasis. VEGF-C may play a role in disorders involving the lymphatic system and may be of potential use in therapeutic lymphangiogenesis.

M. Jeltsch, A. Kaipainen, V. Joukov, K. Alitalo, Molecular/Cancer Biology Laboratory, Haartman Institute, Post Office Box 21 (Haartmaninkatu 3), University of Helsinki, SF-00014 Helsinki, Finland.
X. Meng, M. Lakso, H. Rauvala, Biotechnology Institute, 00014 University of Helsinki, Helsinki, Finland.
M. Swartz, D. Fukumura, R. K. Jain, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
*   These authors contributed equally to this work.

dagger    To whom correspondence should be addressed. E-mail: Kari.Alitalo@Helsinki.FI

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Abnormal lymphatic vessel development in neuropilin 2 mutant mice.
L. Yuan, D. Moyon, L. Pardanaud, C. Breant, M. J. Karkkainen, K. Alitalo, and A. Eichmann (2003)
Development 129, 4797-4806
   Abstract »    Full Text »    PDF »
Up-regulation of Vascular Endothelial Growth Factor C in Breast Cancer Cells by Heregulin-beta 1. A CRITICAL ROLE OF p38/NUCLEAR FACTOR-kappa B SIGNALING PATHWAY.
P.-W. Tsai, S.-G. Shiah, M.-T. Lin, C.-W. Wu, and M.-L. Kuo (2003)
J. Biol. Chem. 278, 5750-5759
   Abstract »    Full Text »    PDF »
Differential in Vivo and in Vitro Expression of Vascular Endothelial Growth Factor (VEGF)-C and VEGF-D in Tumors and Its Relationship to Lymphatic Metastasis in Immunocompetent Rats.
J. Krishnan, V. Kirkin, A. Steffen, M. Hegen, D. Weih, S. Tomarev, J. Wilting, and J. P. Sleeman (2003)
Cancer Res. 63, 713-722
   Abstract »    Full Text »    PDF »
The bloody fate of endothelial stem cells.
H. Kubo and K. Alitalo (2003)
Genes & Dev. 17, 322-329
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Micro-magnetic Resonance Lymphangiography in Mice Using a Novel Dendrimer-based Magnetic Resonance Imaging Contrast Agent.
H. Kobayashi, S. Kawamoto, R. A. Star, T. A. Waldmann, Y. Tagaya, and M. W. Brechbiel (2003)
Cancer Res. 63, 271-276
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Expression of Vascular Endothelial Growth Factor C and D (VEGF-C and -D) is an Important Risk Factor for Lymphatic Metastasis in Undifferentiated Early Gastric Carcinoma.
M. Ishikawa, J. Kitayama, S. Kazama, and H. Nagawa (2003)
Jpn. J. Clin. Oncol. 33, 21-27
   Abstract »    Full Text »    PDF »
VEGFR-3 and CD133 identify a population of CD34+ lymphatic/vascular endothelial precursor cells.
P. Salven, S. Mustjoki, R. Alitalo, K. Alitalo, and S. Rafii (2003)
Blood 101, 168-172
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Vascular Endothelial Growth Factor Secretion by Tumor-infiltrating Macrophages Essentially Supports Tumor Angiogenesis, and IgG Immune Complexes Potentiate the Process.
E. Barbera-Guillem, J. K. Nyhus, C. C. Wolford, C. R. Friece, and J. W. Sampsel (2002)
Cancer Res. 62, 7042-7049
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Vascular Permeability Factor/Vascular Endothelial Growth Factor: A Critical Cytokine in Tumor Angiogenesis and a Potential Target for Diagnosis and Therapy.
H. F. Dvorak (2002)
J. Clin. Oncol. 20, 4368-4380
   Abstract »    Full Text »    PDF »
Lymphangiogenic Gene Therapy With Minimal Blood Vascular Side Effects.
A. Saaristo, T. Veikkola, T. Tammela, B. Enholm, M. J. Karkkainen, K. Pajusola, H. Bueler, S. Yla-Herttuala, and K. Alitalo (2002)
J. Exp. Med. 196, 719-730
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Tumor-Associated Macrophages Express Lymphatic Endothelial Growth Factors and Are Related to Peritumoral Lymphangiogenesis.
S. F. Schoppmann, P. Birner, J. Stockl, R. Kalt, R. Ullrich, C. Caucig, E. Kriehuber, K. Nagy, K. Alitalo, and D. Kerjaschki (2002)
Am. J. Pathol. 161, 947-956
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The role of tumor lymphangiogenesis in metastatic spread.
S. A. STACKER, M. E. BALDWIN, and M. G. ACHEN (2002)
FASEB J 16, 922-934
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Adenoviral VEGF-C overexpression induces blood vessel enlargement, tortuosity, and leakiness but no sprouting angiogenesis in the skin or mucous membranes.
A. SAARISTO, T. VEIKKOLA, B. ENHOLM, M. HYTONEN, J. AROLA, K. PAJUSOLA, P. TURUNEN, M. JELTSCH, M. J. KARKKAINEN, D. KERJASCHKI, et al. (2002)
FASEB J 16, 1041-1049
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