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Apelin-VEGF-C mRNA delivery as therapeutic for the treatment of secondary lymphedema.
Creff, Justine; Lamaa, Asalaa; Benuzzi, Emeline; Balzan, Elisa; Pujol, Francoise; Draia-Nicolau, Tangra; Nougué, Manon; Verdu, Lena; Morfoisse, Florent; Lacazette, Eric; Valet, Philippe; Chaput, Benoit; Gross, Fabian; Gayon, Regis; Bouillé, Pascale; Malloizel-Delaunay, Julie; Bura-Rivière, Alessandra; Prats, Anne-Catherine; Garmy-Susini, Barbara.
Afiliação
  • Creff J; I2MC, Université de Toulouse, Inserm UMR 1297, UT3, Toulouse, France.
  • Lamaa A; I2MC, Université de Toulouse, Inserm UMR 1297, UT3, Toulouse, France.
  • Benuzzi E; I2MC, Université de Toulouse, Inserm UMR 1297, UT3, Toulouse, France.
  • Balzan E; I2MC, Université de Toulouse, Inserm UMR 1297, UT3, Toulouse, France.
  • Pujol F; I2MC, Université de Toulouse, Inserm UMR 1297, UT3, Toulouse, France.
  • Draia-Nicolau T; I2MC, Université de Toulouse, Inserm UMR 1297, UT3, Toulouse, France.
  • Nougué M; I2MC, Université de Toulouse, Inserm UMR 1297, UT3, Toulouse, France.
  • Verdu L; I2MC, Université de Toulouse, Inserm UMR 1297, UT3, Toulouse, France.
  • Morfoisse F; I2MC, Université de Toulouse, Inserm UMR 1297, UT3, Toulouse, France.
  • Lacazette E; I2MC, Université de Toulouse, Inserm UMR 1297, UT3, Toulouse, France.
  • Valet P; Institut RESTORE, UMR 1301-INSERM, 5070-CNRS, Université Paul Sabatier, Université de Toulouse, Toulouse, France.
  • Chaput B; Department of Plastic Surgery, University of Toulouse III Paul Sabatier, Toulouse, France.
  • Gross F; Biotherapy Module of Clinical Investigation Center (CIC 1436), University Hospital of Toulouse, 31059, Toulouse, France.
  • Gayon R; Flash Therapeutics, Toulouse, France.
  • Bouillé P; Flash Therapeutics, Toulouse, France.
  • Malloizel-Delaunay J; Service de Médecine Vasculaire, Centre Hospitalier Universitaire de Toulouse, Toulouse, France.
  • Bura-Rivière A; Service de Médecine Vasculaire, Centre Hospitalier Universitaire de Toulouse, Toulouse, France.
  • Prats AC; I2MC, Université de Toulouse, Inserm UMR 1297, UT3, Toulouse, France.
  • Garmy-Susini B; I2MC, Université de Toulouse, Inserm UMR 1297, UT3, Toulouse, France. barbara.garmy-susini@inserm.fr.
EMBO Mol Med ; 16(2): 386-415, 2024 Feb.
Article em En | MEDLINE | ID: mdl-38177539
ABSTRACT
Secondary lymphedema (LD) corresponds to a severe lymphatic dysfunction leading to the accumulation of fluid and fibrotic adipose tissue in a limb. Here, we identified apelin (APLN) as a powerful molecule for regenerating lymphatic function in LD. We identified the loss of APLN expression in the lymphedematous arm compared to the normal arm in patients. The role of APLN in LD was confirmed in APLN knockout mice, in which LD is increased and associated with fibrosis and dermal backflow. This was reversed by intradermal injection of APLN-lentivectors. Mechanistically, APLN stimulates lymphatic endothelial cell gene expression and induces the binding of E2F8 transcription factor to the promoter of CCBE1 that controls VEGF-C processing. In addition, APLN induces Akt and eNOS pathways to stimulate lymphatic collector pumping. Our results show that APLN represents a novel partner for VEGF-C to restore lymphatic function in both initial and collecting vessels. As LD appears after cancer treatment, we validated the APLN-VEGF-C combination using a novel class of nonintegrative RNA delivery LentiFlash® vector that will be evaluated for phase I/IIa clinical trial.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Fator C de Crescimento do Endotélio Vascular / Linfedema Tipo de estudo: Clinical_trials / Prognostic_studies Limite: Animals / Humans Idioma: En Revista: EMBO Mol Med Assunto da revista: BIOLOGIA MOLECULAR Ano de publicação: 2024 Tipo de documento: Article País de afiliação: França

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Fator C de Crescimento do Endotélio Vascular / Linfedema Tipo de estudo: Clinical_trials / Prognostic_studies Limite: Animals / Humans Idioma: En Revista: EMBO Mol Med Assunto da revista: BIOLOGIA MOLECULAR Ano de publicação: 2024 Tipo de documento: Article País de afiliação: França