VEGF-C gene therapy augments postnatal lymphangiogenesis and ameliorates secondary lymphedema
Young-sup Yoon, … , Jeffrey M. Isner, Douglas W. Losordo
Young-sup Yoon, … , Jeffrey M. Isner, Douglas W. Losordo
Published March 1, 2003
Citation Information: J Clin Invest. 2003;111(5):717-725. https://doi.org/10.1172/JCI15830.
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Article Genetics

VEGF-C gene therapy augments postnatal lymphangiogenesis and ameliorates secondary lymphedema

Abstract

Although lymphedema is a common clinical condition, treatment for this disabling condition remains limited and largely ineffective. Recently, it has been reported that overexpression of VEGF-C correlates with increased lymphatic vessel growth (lymphangiogenesis). However, the effect of VEGF-C–induced lymphangiogenesis on lymphedema has yet to be demonstrated. Here we investigated the impact of local transfer of naked plasmid DNA encoding human VEGF-C (phVEGF-C) on two animal models of lymphedema: one in the rabbit ear and the other in the mouse tail. In a rabbit model, following local phVEGF-C gene transfer, VEGFR-3 expression was significantly increased. This gene transfer led to a decrease in thickness and volume of lymphedema, improvement of lymphatic function demonstrated by serial lymphoscintigraphy, and finally, attenuation of the fibrofatty changes of the skin, the final consequences of lymphedema. The favorable effect of phVEGF-C on lymphedema was reconfirmed in a mouse tail model. Immunohistochemical analysis using lymphatic-specific markers: VEGFR-3, lymphatic endothelial hyaluronan receptor-1, together with the proliferation marker Ki-67 Ab revealed that phVEGF-C transfection potently induced new lymphatic vessel growth. This study, we believe for the first time, documents that gene transfer of phVEGF-C resolves lymphedema through direct augmentation of lymphangiogenesis. This novel therapeutic strategy may merit clinical investigation in patients with lymphedema.

Authors

Young-sup Yoon, Toshinori Murayama, Edwin Gravereaux, Tengiz Tkebuchava, Marcy Silver, Cynthia Curry, Andrea Wecker, Rudolf Kirchmair, Chun Song Hu, Marianne Kearney, Alan Ashare, David G. Jackson, Hajime Kubo, Jeffrey M. Isner, Douglas W. Losordo

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Figure 4

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(a) Gene transfer of phVEGF-C decreases lymphedema in a mouse tail model...
(a) Gene transfer of phVEGF-C decreases lymphedema in a mouse tail model of lymphedema. Tail thickness was significantly greater in the operated tail than in the unoperated tail during the entire 5 weeks. In the VEGF-C group, compared with the saline, LacZ, and VEGF165 groups, the tail thickness was significantly smaller at 3–5 weeks (*P < 0.05). No-op, no operation. (b–m) phVEGF-C induces lymphangiogenesis in a mouse tail model of lymphedema. (b–k) Immunohistochemistry using markers of lymphatic endothelium, LYVE-1 (b–f), and VEGFR-3 (g–k), in normal (b and g) and operated (3 weeks after lymphedema surgery) skin sections from the saline (c and h), LacZ (d and i), VEGF-C (e and j), and VEGF165 (f and k) groups. Lymphatic vessels are seen as brown color (black arrows). Note the abundance of hyperplastic lymphatic vessels in phVEGF-C–transfected sections (e and j). l and m show quantification of LYVE-1– and VEGFR-3–positive lymphatic vessels. Compared with normal and control (saline, LacZ, and VEGF165) groups, the VEGF-C group showed significantly higher lymphatic vessel density. *P < 0.05 vs. normal; **P < 0.01 vs. LE-saline and LE-LacZ. Scale bar, 100 μm.