title: 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.affiliation: Department of Vascular Medicine, St. Elizabeth's Medical Center, Tufts University School of Medicine, Boston, Massachusetts, USA.
authors.forename: Young-Sup
authors.initials: YS
authors.lastname: Yoon
authors.forename: Toshinori
authors.initials: T
authors.lastname: Murayama
authors.forename: Edwin
authors.initials: E
authors.lastname: Gravereaux
authors.forename: Tengiz
authors.initials: T
authors.lastname: Tkebuchava
authors.forename: Marcy
authors.initials: M
authors.lastname: Silver
authors.forename: Cynthia
authors.initials: C
authors.lastname: Curry
authors.forename: Andrea
authors.initials: A
authors.lastname: Wecker
authors.forename: Rudolf
authors.initials: R
authors.lastname: Kirchmair
authors.forename: Chun Song
authors.initials: CS
authors.lastname: Hu
authors.forename: Marianne
authors.initials: M
authors.lastname: Kearney
authors.forename: Alan
authors.initials: A
authors.lastname: Ashare
authors.forename: David G
authors.initials: DG
authors.lastname: Jackson
authors.forename: Hajime
authors.initials: H
authors.lastname: Kubo
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Isner
authors.forename: Douglas W
authors.initials: DW
authors.lastname: Losordo
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D004195:Disease Models, Animal; D016228:Endothelial Growth Factors / Q000235:genetics*; D015316:Genetic Therapy; D007150:Immunohistochemistry; D008208:Lymphatic System / Q000502:physiology*; D008209:Lymphedema / Q000628:therapy*; D008969:Molecular Sequence Data; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D010766:Phosphorylation; D011817:Rabbits; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019076:Transgenes; D042582:Vascular Endothelial Growth Factor C; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000235:genetics / Q000378:metabolism
chemical_list: D016228:Endothelial Growth Factors; D042582:Vascular Endothelial Growth Factor C; D040301:Vascular Endothelial Growth Factor Receptor-2; D040321:Vascular Endothelial Growth Factor Receptor-3