Nature Medicine
7, 199 - 205 (2001)
doi:10.1038/84651
Inhibition of lymphangiogenesis with resulting lymphedema in transgenic mice expressing soluble VEGF receptor-3Taija Mäkinen1, Lotta Jussila1, Tanja Veikkola1, Terhi Karpanen1, Mikko I. Kettunen2, Kalevi J. Pulkkanen3, 4, Risto Kauppinen2, David G. Jackson5, Hajime Kubo6, Shin-Ichi Nishikawa6, Seppo Ylä-Herttuala3
& Kari Alitalo11
Molecular/Cancer Biology Laboratory and Ludwig Institute for Cancer Research, Haartman Institute, University of Helsinki, Helsinki, Finland
2
National Bio-NMR Facility, A.I. Virtanen Institute, University of Kuopio, Kuopio, Finland
3
Department of Molecular Medicine, A.I. Virtanen Institute, University of Kuopio, Kuopio, Finland
4
Department of Oncology, Kuopio University Hospital, Kuopio, Finland
5
University of Oxford, Molecular Immunology Group, Nuffield Department of Medicine, Headington, Oxford, United Kingdom
6
Department of Molecular Genetics, Kyoto University, Japan
Correspondence should be addressed to Kari Alitalo kari.alitalo@helsinki.fiThe lymphatic vasculature transports extravasated tissue fluid, macromolecules and cells back into the blood circulation. Recent reports have focused on the molecular mechanisms regulating the lymphatic vessels. Vascular endothelial growth factor (VEGF)-C and VEGF-D have been shown to stimulate lymphangiogenesis and their receptor, VEGFR-3, has been linked to human hereditary lymphedema. Here we show that a soluble form of VEGFR-3 is a potent inhibitor of VEGF-C/VEGF-D signaling, and when expressed in the skin of transgenic mice, it inhibits fetal lymphangiogenesis and induces a regression of already formed lymphatic vessels, though the blood vasculature remains normal. Transgenic mice develop a lymphedema-like phenotype characterized by swelling of feet, edema and dermal fibrosis. They survive the neonatal period in spite of a virtually complete lack of lymphatic vessels in several tissues, and later show regeneration of the lymphatic vasculature, indicating that induction of lymphatic regeneration may also be possible in humans.
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