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Article
Nature Immunology  5, 74 - 80 (2003)
Published online: 23 November 2003; | doi:10.1038/ni1013

Vascular endothelial growth factor C is required for sprouting of the first lymphatic vessels from embryonic veins

Marika J Karkkainen1, Paula Haiko1, Kirsi Sainio2, Juha Partanen3, Jussi Taipale1, Tatiana V Petrova1, Michael Jeltsch1, David G Jackson4, Marja Talikka5, Heikki Rauvala5, Christer Betsholtz6 & Kari Alitalo1

1  Molecular/Cancer Biology Laboratory and Ludwig Institute for Cancer Research, Haartman Institute and Helsinki University Hospital, Biomedicum Helsinki, University of Helsinki, PO Box 63, 00014 Helsinki, Finland.

2  Institute of Biomedicine, Developmental Biology, Biomedicum Helsinki and HUCH-diagnostics, PO Box 400, 00029 Helsinki, Finland.

3  Institute of Biotechnology, University of Helsinki, PO Box 56, 00014 Helsinki, Finland.

4  MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Headington, Oxford, UK.

5  Neuroscience Center, University of Helsinki, PO Box 56, 00014 Helsinki, Finland.

6  Department of Medical Biochemistry, University of Gothenburg, Box 440, 405 30 Gothenburg, Sweden.

Correspondence should be addressed to Kari Alitalo kari.alitalo@helsinki.fi
Lymphatic vessels are essential for immune surveillance, tissue fluid homeostasis and fat absorption. Defects in lymphatic vessel formation or function cause lymphedema. Here we show that the vascular endothelial growth factor C (VEGF-C) is required for the initial steps in lymphatic development. In Vegfc-/- mice, endothelial cells commit to the lymphatic lineage but do not sprout to form lymph vessels. Sprouting was rescued by VEGF-C and VEGF-D but not by VEGF, indicating VEGF receptor 3 specificity. The lack of lymphatic vessels resulted in prenatal death due to fluid accumulation in tissues, and Vegfc+/- mice developed cutaneous lymphatic hypoplasia and lymphedema. Our results indicate that VEGF-C is the paracrine factor essential for lymphangiogenesis, and show that both Vegfc alleles are required for normal lymphatic development.

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Nature Immunology
ISSN: 1529-2908
EISSN: 1529-2916
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