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Inhibition of lymphangiogenesis with resulting lymphedema in transgenic mice expressing soluble VEGF receptor-3

Abstract

The 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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Figure 1: Soluble VEGFR-3 inhibits ligand-dependent receptor signaling.
Figure 2: K14-VEGFR-3–Ig mice lack dermal lymphatic vessels.
Figure 3: Soluble VEGFR-3 inhibits lymphangiogenesis specifically.
Figure 4: Circulating levels of soluble VEGFR-3 inhibit lymphatic vessel development in internal organs.
Figure 5: Features of human lymphedema in the K14-VEGFR-3–Ig mice.
Figure 6: Soluble VEGFR-3 leads to a regression of the lymphatic vessels in embryonic skin.

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Acknowledgements

We thank G. Thurston and D. McDonald for teaching the lectin staining. J Jänne, L. Alhonen, M. Jänne and H. Rauvala for help in the generation of the transgenic mice; I. Seppälä for advice on ELISA; and T. Tainola, P. Ylikantola, S. Karttunen, R. Kivirikko and K. Makkonen for technical assistance. The K14 vector was a gift from E. Fuchs. This study was supported by grants from the Finnish Cancer Organization, Ida Montini Foundation, Finnish Cultural Foundation and Paulo Foundation.

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Correspondence to Kari Alitalo.

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Mäkinen, T., Jussila, L., Veikkola, T. et al. Inhibition of lymphangiogenesis with resulting lymphedema in transgenic mice expressing soluble VEGF receptor-3. Nat Med 7, 199–205 (2001). https://doi.org/10.1038/84651

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