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

Nature Immunology volume 5, pages 74–80 (2004)Cite this article

Abstract

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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Figure 1: Genetic targeting of the Vegfc locus.
Figure 2: Vegfc expression is associated with lymphatic vascular development.
Figure 3: Vegfc deficiency results in failure of lymphatic vascular development.
Figure 4: VEGF-C is required for migration of Prox-1-expressing endothelial cells.
Figure 5: Developmental and functional defects of the lymphatic vessels in Vegfc+/− mice.

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Acknowledgements

We thank K. Karila and E. Valdre for their help in generating mice; S. Nuutinen and M. Jauhiainen for analysis of chylous fluid; H. Kubo, E. Ruoslahti, M. Quintanilla, H. Kowalski and D. Kerjaschki for antibodies; and T. Tainola, S. Karttunen, K. Makkonen, A. Parsons, P. Hyvarinen, M. Pajuportti, A. Flint and A. Vihera for technical assistance. Supported by grants from the Finnish Cancer Organizations, Academy of Finland (202852 and 204312), Novo Nordisk Foundation, Helsinki University Hospital Funds (TYH2301 and TYH1313), The Human Frontier Science Foundation, the European Union (Angionet QLC1-CT-2001-01172) and National Institutes of Health (HD37243).

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Authors and Affiliations

  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, Helsinki, 00014, Finland

    Marika J Karkkainen, Paula Haiko, Jussi Taipale, Tatiana V Petrova, Michael Jeltsch & Kari Alitalo

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

    Kirsi Sainio

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

    Juha Partanen

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

    David G Jackson

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

    Marja Talikka & Heikki Rauvala

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

    Christer Betsholtz

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  1. Marika J Karkkainen
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Correspondence to Kari Alitalo.

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Karkkainen, M., Haiko, P., Sainio, K. et al. Vascular endothelial growth factor C is required for sprouting of the first lymphatic vessels from embryonic veins. Nat Immunol 5, 74–80 (2004). https://doi.org/10.1038/ni1013

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