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

Youngsup 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

Research output: Contribution to journalArticle

182 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)717-725
Number of pages9
JournalJournal of Clinical Investigation
Volume111
Issue number5
DOIs
Publication statusPublished - 2003 Jan 1

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Lymphangiogenesis
Vascular Endothelial Growth Factor C
Lymphedema
Genetic Therapy
Plasmids
Vascular Endothelial Growth Factor Receptor-3
DNA
Lymphatic Vessels
Tail
CD44 Antigens
Genes
Rabbits
Lymphoscintigraphy
Growth
Transfection
Ear
Animal Models
Skin

All Science Journal Classification (ASJC) codes

  • Medicine(all)

Cite this

Yoon, Y., Murayama, T., Gravereaux, E., Tkebuchava, T., Silver, M., Curry, C., ... Losordo, D. W. (2003). VEGF-C gene therapy augments postnatal lymphangiogenesis and ameliorates secondary lymphedema. Journal of Clinical Investigation, 111(5), 717-725. https://doi.org/10.1172/JCI15830
Yoon, Youngsup ; Murayama, Toshinori ; Gravereaux, Edwin ; Tkebuchava, Tengiz ; Silver, Marcy ; Curry, Cynthia ; Wecker, Andrea ; Kirchmair, Rudolf ; Hu, Chun Song ; Kearney, Marianne ; Ashare, Alan ; Jackson, David G. ; Kubo, Hajime ; Isner, Jeffrey M. ; Losordo, Douglas W. / VEGF-C gene therapy augments postnatal lymphangiogenesis and ameliorates secondary lymphedema. In: Journal of Clinical Investigation. 2003 ; Vol. 111, No. 5. pp. 717-725.
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Yoon, Y, Murayama, T, Gravereaux, E, Tkebuchava, T, Silver, M, Curry, C, Wecker, A, Kirchmair, R, Hu, CS, Kearney, M, Ashare, A, Jackson, DG, Kubo, H, Isner, JM & Losordo, DW 2003, 'VEGF-C gene therapy augments postnatal lymphangiogenesis and ameliorates secondary lymphedema', Journal of Clinical Investigation, vol. 111, no. 5, pp. 717-725. https://doi.org/10.1172/JCI15830

VEGF-C gene therapy augments postnatal lymphangiogenesis and ameliorates secondary lymphedema. / Yoon, Youngsup; Murayama, Toshinori; Gravereaux, Edwin; Tkebuchava, Tengiz; Silver, Marcy; Curry, Cynthia; Wecker, Andrea; Kirchmair, Rudolf; Hu, Chun Song; Kearney, Marianne; Ashare, Alan; Jackson, David G.; Kubo, Hajime; Isner, Jeffrey M.; Losordo, Douglas W.

In: Journal of Clinical Investigation, Vol. 111, No. 5, 01.01.2003, p. 717-725.

Research output: Contribution to journalArticle

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T1 - VEGF-C gene therapy augments postnatal lymphangiogenesis and ameliorates secondary lymphedema

AU - Yoon, Youngsup

AU - Murayama, Toshinori

AU - Gravereaux, Edwin

AU - Tkebuchava, Tengiz

AU - Silver, Marcy

AU - Curry, Cynthia

AU - Wecker, Andrea

AU - Kirchmair, Rudolf

AU - Hu, Chun Song

AU - Kearney, Marianne

AU - Ashare, Alan

AU - Jackson, David G.

AU - Kubo, Hajime

AU - Isner, Jeffrey M.

AU - Losordo, Douglas W.

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N2 - 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.

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