VEGF-C gene therapy augments postnatal lymphangiogenesis and ameliorates secondary lymphedema
Identifieur interne : 008D71 ( Main/Exploration ); précédent : 008D70; suivant : 008D72VEGF-C gene therapy augments postnatal lymphangiogenesis and ameliorates secondary lymphedema
Auteurs : Young-Sup Yoon ; Toshinori Murayama ; Edwin Gravereaux ; Tengiz Tkebuchava ; Marcy Silver ; Cynthia Curry ; Andrea Wecker ; Rudolf Kirchmair ; Chun Song Hu ; Marianne Kearney ; Alan Ashare [États-Unis] ; David G. Jackson [Royaume-Uni] ; Hajime Kubo [Finlande] ; Jeffrey M. Isner ; Douglas W. LosordoSource :
- Journal of Clinical Investigation [ 0021-9738 ] ; 2003.
Descripteurs français
- KwdFr :
- Animaux, Données de séquences moléculaires, Facteur de croissance endothéliale vasculaire de type C, Facteurs de croissance endothéliale (génétique), Immunohistochimie, Lapins, Lymphoedème (), Modèles animaux de maladie humaine, Néovascularisation physiologique (), Phosphorylation, RT-PCR, Récepteur-2 au facteur croissance endothéliale vasculaire (métabolisme), Récepteur-3 au facteur croissance endothéliale vasculaire (génétique), Récepteur-3 au facteur croissance endothéliale vasculaire (métabolisme), Système lymphatique (physiologie), Séquence d'acides aminés, Thérapie génétique, Transgènes.
- MESH :
- génétique : Facteurs de croissance endothéliale, Récepteur-3 au facteur croissance endothéliale vasculaire.
- métabolisme : Récepteur-2 au facteur croissance endothéliale vasculaire, Récepteur-3 au facteur croissance endothéliale vasculaire.
- physiologie : Système lymphatique.
- Animaux, Données de séquences moléculaires, Facteur de croissance endothéliale vasculaire de type C, Immunohistochimie, Lapins, Lymphoedème, Modèles animaux de maladie humaine, Néovascularisation physiologique, Phosphorylation, RT-PCR, Séquence d'acides aminés, Thérapie génétique, Transgènes.
English descriptors
- KwdEn :
- Amino Acid Sequence, Animals, Disease Models, Animal, Endothelial Growth Factors (genetics), Genetic Therapy, Immunohistochemistry, Lymphatic System (physiology), Lymphedema (therapy), Molecular Sequence Data, Neovascularization, Physiologic (drug effects), Phosphorylation, Rabbits, Reverse Transcriptase Polymerase Chain Reaction, Transgenes, Vascular Endothelial Growth Factor C, Vascular Endothelial Growth Factor Receptor-2 (metabolism), Vascular Endothelial Growth Factor Receptor-3 (genetics), Vascular Endothelial Growth Factor Receptor-3 (metabolism).
- MESH :
- chemical , genetics : Endothelial Growth Factors, Vascular Endothelial Growth Factor Receptor-3.
- drug effects : Neovascularization, Physiologic.
- chemical , metabolism : Vascular Endothelial Growth Factor Receptor-2, Vascular Endothelial Growth Factor Receptor-3.
- physiology : Lymphatic System.
- therapy : Lymphedema.
- Amino Acid Sequence, Animals, Disease Models, Animal, Genetic Therapy, Immunohistochemistry, Molecular Sequence Data, Phosphorylation, Rabbits, Reverse Transcriptase Polymerase Chain Reaction, Transgenes, Vascular Endothelial Growth Factor C.
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.
Url:
DOI: 10.1172/JCI200315830
PubMed: 12618526
PubMed Central: 151891
Affiliations:
- Finlande, Royaume-Uni, États-Unis
- Angleterre, Massachusetts, Oxfordshire, Uusimaa
- Helsinki, Oxford
- Université d'Helsinki, Université d'Oxford
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lymphedema</title><author><name sortKey="Yoon, Young Sup" sort="Yoon, Young Sup" uniqKey="Yoon Y" first="Young-Sup" last="Yoon">Young-Sup Yoon</name><affiliation><nlm:aff wicri:cut=", and" id="N0x9c934d8.0x8be8450">Department of Vascular Medicine and Department of Cardiovascular Research</nlm:aff></affiliation></author><author><name sortKey="Murayama, Toshinori" sort="Murayama, Toshinori" uniqKey="Murayama T" first="Toshinori" last="Murayama">Toshinori Murayama</name><affiliation><nlm:aff wicri:cut=", and" id="N0x9c934d8.0x8be8450">Department of Vascular Medicine and Department of Cardiovascular Research</nlm:aff></affiliation></author><author><name sortKey="Gravereaux, Edwin" sort="Gravereaux, Edwin" uniqKey="Gravereaux E" first="Edwin" last="Gravereaux">Edwin Gravereaux</name><affiliation><nlm:aff wicri:cut=", and" id="N0x9c934d8.0x8be8450">Department of Vascular Medicine and Department of Cardiovascular Research</nlm:aff></affiliation></author><author><name sortKey="Tkebuchava, Tengiz" sort="Tkebuchava, Tengiz" uniqKey="Tkebuchava T" first="Tengiz" last="Tkebuchava">Tengiz Tkebuchava</name><affiliation><nlm:aff wicri:cut=", and" id="N0x9c934d8.0x8be8450">Department of Vascular Medicine and Department of Cardiovascular Research</nlm:aff></affiliation></author><author><name sortKey="Silver, Marcy" sort="Silver, Marcy" uniqKey="Silver M" first="Marcy" last="Silver">Marcy Silver</name><affiliation><nlm:aff wicri:cut=", and" id="N0x9c934d8.0x8be8450">Department of Vascular Medicine and Department of Cardiovascular Research</nlm:aff></affiliation></author><author><name sortKey="Curry, Cynthia" sort="Curry, Cynthia" uniqKey="Curry C" first="Cynthia" last="Curry">Cynthia Curry</name><affiliation><nlm:aff wicri:cut=", and" id="N0x9c934d8.0x8be8450">Department of Vascular Medicine and Department of Cardiovascular Research</nlm:aff></affiliation></author><author><name sortKey="Wecker, Andrea" sort="Wecker, Andrea" uniqKey="Wecker A" first="Andrea" last="Wecker">Andrea Wecker</name><affiliation><nlm:aff wicri:cut=", and" id="N0x9c934d8.0x8be8450">Department of Vascular Medicine and Department of Cardiovascular Research</nlm:aff></affiliation></author><author><name sortKey="Kirchmair, Rudolf" sort="Kirchmair, Rudolf" uniqKey="Kirchmair R" first="Rudolf" last="Kirchmair">Rudolf Kirchmair</name><affiliation><nlm:aff wicri:cut=", and" id="N0x9c934d8.0x8be8450">Department of Vascular Medicine and Department of Cardiovascular Research</nlm:aff></affiliation></author><author><name sortKey="Hu, Chun Song" sort="Hu, Chun Song" uniqKey="Hu C" first="Chun Song" last="Hu">Chun Song Hu</name><affiliation><nlm:aff wicri:cut=", and" id="N0x9c934d8.0x8be8450">Department of Vascular Medicine and Department of Cardiovascular Research</nlm:aff></affiliation></author><author><name sortKey="Kearney, Marianne" sort="Kearney, Marianne" uniqKey="Kearney M" first="Marianne" last="Kearney">Marianne Kearney</name><affiliation><nlm:aff wicri:cut=", and" id="N0x9c934d8.0x8be8450">Department of Vascular Medicine and Department of Cardiovascular Research</nlm:aff></affiliation></author><author><name sortKey="Ashare, Alan" sort="Ashare, Alan" uniqKey="Ashare A" first="Alan" last="Ashare">Alan Ashare</name><affiliation wicri:level="2"><nlm:aff id="N0x9c934d8.0x8be8450"> Department of Nuclear Medicine, St. Elizabeth’s Medical Center, Tufts University School of Medicine, Boston, Massachusetts, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea> Department of Nuclear Medicine, St. Elizabeth’s Medical Center, Tufts University School of Medicine, Boston, Massachusetts</wicri:regionArea><placeName><region type="state">Massachusetts</region></placeName></affiliation></author><author><name sortKey="Jackson, David G" sort="Jackson, David G" uniqKey="Jackson D" first="David G." last="Jackson">David G. Jackson</name><affiliation wicri:level="4"><nlm:aff id="N0x9c934d8.0x8be8450"> Molecular Immunology Group, Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom</nlm:aff><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea> Molecular Immunology Group, Institute of Molecular Medicine, University of Oxford, Oxford</wicri:regionArea><placeName><settlement type="city">Oxford</settlement><region type="country">Angleterre</region><region type="comté" nuts="2">Oxfordshire</region><settlement type="city">Oxford</settlement></placeName><orgName type="university">Université d'Oxford</orgName></affiliation></author><author><name sortKey="Kubo, Hajime" sort="Kubo, Hajime" uniqKey="Kubo H" first="Hajime" last="Kubo">Hajime Kubo</name><affiliation wicri:level="4"><nlm:aff id="N0x9c934d8.0x8be8450"> Molecular/Cancer Biology Laboratory, Haartman Institute, University of Helsinki, Helsinki, Finland</nlm:aff><country xml:lang="fr">Finlande</country><wicri:regionArea> Molecular/Cancer Biology Laboratory, Haartman Institute, University of Helsinki, Helsinki</wicri:regionArea><orgName type="university">Université d'Helsinki</orgName><placeName><settlement type="city">Helsinki</settlement><region type="région" nuts="2">Uusimaa</region></placeName></affiliation></author><author><name sortKey="Isner, Jeffrey M" sort="Isner, Jeffrey M" uniqKey="Isner J" first="Jeffrey M." last="Isner">Jeffrey M. Isner</name><affiliation><nlm:aff wicri:cut=", and" id="N0x9c934d8.0x8be8450">Department of Vascular Medicine and Department of Cardiovascular Research</nlm:aff></affiliation></author><author><name sortKey="Losordo, Douglas W" sort="Losordo, Douglas W" uniqKey="Losordo D" first="Douglas W." last="Losordo">Douglas W. Losordo</name><affiliation><nlm:aff wicri:cut=", and" id="N0x9c934d8.0x8be8450">Department of Vascular Medicine and Department of Cardiovascular Research</nlm:aff></affiliation></author></analytic><series><title level="j">Journal of Clinical Investigation</title><idno type="ISSN">0021-9738</idno><imprint><date when="2003">2003</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Amino Acid Sequence</term><term>Animals</term><term>Disease Models, Animal</term><term>Endothelial Growth Factors (genetics)</term><term>Genetic Therapy</term><term>Immunohistochemistry</term><term>Lymphatic System (physiology)</term><term>Lymphedema (therapy)</term><term>Molecular Sequence Data</term><term>Neovascularization, Physiologic (drug effects)</term><term>Phosphorylation</term><term>Rabbits</term><term>Reverse Transcriptase Polymerase Chain Reaction</term><term>Transgenes</term><term>Vascular Endothelial Growth Factor C</term><term>Vascular Endothelial Growth Factor Receptor-2 (metabolism)</term><term>Vascular Endothelial Growth Factor Receptor-3 (genetics)</term><term>Vascular Endothelial Growth Factor Receptor-3 (metabolism)</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Animaux</term><term>Données de séquences moléculaires</term><term>Facteur de croissance endothéliale vasculaire de type C</term><term>Facteurs de croissance endothéliale (génétique)</term><term>Immunohistochimie</term><term>Lapins</term><term>Lymphoedème ()</term><term>Modèles animaux de maladie humaine</term><term>Néovascularisation physiologique ()</term><term>Phosphorylation</term><term>RT-PCR</term><term>Récepteur-2 au facteur croissance endothéliale vasculaire (métabolisme)</term><term>Récepteur-3 au facteur croissance endothéliale vasculaire (génétique)</term><term>Récepteur-3 au facteur croissance endothéliale vasculaire (métabolisme)</term><term>Système lymphatique (physiologie)</term><term>Séquence d'acides aminés</term><term>Thérapie génétique</term><term>Transgènes</term></keywords><keywords scheme="MESH" type="chemical" qualifier="genetics" xml:lang="en"><term>Endothelial Growth Factors</term><term>Vascular Endothelial Growth Factor Receptor-3</term></keywords><keywords scheme="MESH" qualifier="drug effects" xml:lang="en"><term>Neovascularization, Physiologic</term></keywords><keywords scheme="MESH" qualifier="génétique" xml:lang="fr"><term>Facteurs de croissance endothéliale</term><term>Récepteur-3 au facteur croissance endothéliale vasculaire</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Vascular Endothelial Growth Factor Receptor-2</term><term>Vascular Endothelial Growth Factor Receptor-3</term></keywords><keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>Récepteur-2 au facteur croissance endothéliale vasculaire</term><term>Récepteur-3 au facteur croissance endothéliale vasculaire</term></keywords><keywords scheme="MESH" qualifier="physiologie" xml:lang="fr"><term>Système lymphatique</term></keywords><keywords scheme="MESH" qualifier="physiology" xml:lang="en"><term>Lymphatic System</term></keywords><keywords scheme="MESH" qualifier="therapy" xml:lang="en"><term>Lymphedema</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Amino Acid Sequence</term><term>Animals</term><term>Disease Models, Animal</term><term>Genetic Therapy</term><term>Immunohistochemistry</term><term>Molecular Sequence Data</term><term>Phosphorylation</term><term>Rabbits</term><term>Reverse Transcriptase Polymerase Chain Reaction</term><term>Transgenes</term><term>Vascular Endothelial Growth Factor C</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Animaux</term><term>Données de séquences moléculaires</term><term>Facteur de croissance endothéliale vasculaire de type C</term><term>Immunohistochimie</term><term>Lapins</term><term>Lymphoedème</term><term>Modèles animaux de maladie humaine</term><term>Néovascularisation physiologique</term><term>Phosphorylation</term><term>RT-PCR</term><term>Séquence d'acides aminés</term><term>Thérapie génétique</term><term>Transgènes</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>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.</p></div></front></TEI><affiliations><list><country><li>Finlande</li><li>Royaume-Uni</li><li>États-Unis</li></country><region><li>Angleterre</li><li>Massachusetts</li><li>Oxfordshire</li><li>Uusimaa</li></region><settlement><li>Helsinki</li><li>Oxford</li></settlement><orgName><li>Université d'Helsinki</li><li>Université d'Oxford</li></orgName></list><tree><noCountry><name sortKey="Curry, Cynthia" sort="Curry, Cynthia" uniqKey="Curry C" first="Cynthia" last="Curry">Cynthia Curry</name><name sortKey="Gravereaux, Edwin" sort="Gravereaux, Edwin" uniqKey="Gravereaux E" first="Edwin" last="Gravereaux">Edwin Gravereaux</name><name sortKey="Hu, Chun Song" sort="Hu, Chun Song" uniqKey="Hu C" first="Chun Song" last="Hu">Chun Song Hu</name><name sortKey="Isner, Jeffrey M" sort="Isner, Jeffrey M" uniqKey="Isner J" first="Jeffrey M." last="Isner">Jeffrey M. Isner</name><name sortKey="Kearney, Marianne" sort="Kearney, Marianne" uniqKey="Kearney M" first="Marianne" last="Kearney">Marianne Kearney</name><name sortKey="Kirchmair, Rudolf" sort="Kirchmair, Rudolf" uniqKey="Kirchmair R" first="Rudolf" last="Kirchmair">Rudolf Kirchmair</name><name sortKey="Losordo, Douglas W" sort="Losordo, Douglas W" uniqKey="Losordo D" first="Douglas W." last="Losordo">Douglas W. Losordo</name><name sortKey="Murayama, Toshinori" sort="Murayama, Toshinori" uniqKey="Murayama T" first="Toshinori" last="Murayama">Toshinori Murayama</name><name sortKey="Silver, Marcy" sort="Silver, Marcy" uniqKey="Silver M" first="Marcy" last="Silver">Marcy Silver</name><name sortKey="Tkebuchava, Tengiz" sort="Tkebuchava, Tengiz" uniqKey="Tkebuchava T" first="Tengiz" last="Tkebuchava">Tengiz Tkebuchava</name><name sortKey="Wecker, Andrea" sort="Wecker, Andrea" uniqKey="Wecker A" first="Andrea" last="Wecker">Andrea Wecker</name><name sortKey="Yoon, Young Sup" sort="Yoon, Young Sup" uniqKey="Yoon Y" first="Young-Sup" last="Yoon">Young-Sup Yoon</name></noCountry><country name="États-Unis"><region name="Massachusetts"><name sortKey="Ashare, Alan" sort="Ashare, Alan" uniqKey="Ashare A" first="Alan" last="Ashare">Alan Ashare</name></region></country><country name="Royaume-Uni"><region name="Angleterre"><name sortKey="Jackson, David G" sort="Jackson, David G" uniqKey="Jackson D" first="David G." last="Jackson">David G. Jackson</name></region></country><country name="Finlande"><region name="Uusimaa"><name sortKey="Kubo, Hajime" sort="Kubo, Hajime" uniqKey="Kubo H" first="Hajime" last="Kubo">Hajime Kubo</name></region></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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|texte= VEGF-C gene therapy augments postnatal lymphangiogenesis and ameliorates secondary lymphedema
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