Apelin-VEGF-C mRNA delivery as therapeutic for the treatment of secondary lymphedema

Author:

Creff JustineORCID,Lamaa Asalaa,Benuzzi Emeline,Balzan ElisaORCID,Pujol Francoise,Draia-Nicolau TangraORCID,Nougué Manon,Verdu LenaORCID,Morfoisse FlorentORCID,Lacazette EricORCID,Valet Philippe,Chaput Benoit,Gross FabianORCID,Gayon Regis,Bouillé Pascale,Malloizel-Delaunay Julie,Bura-Rivière AlessandraORCID,Prats Anne-CatherineORCID,Garmy-Susini BarbaraORCID

Abstract

AbstractSecondary 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.

Publisher

Springer Science and Business Media LLC

Subject

Molecular Medicine

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