Apelin-VEGF-C mRNA delivery as therapeutic for the treatment of secondary lymphedema.
Apelin
Collector
VEGF-C
lymphedema
mRNA
Journal
EMBO molecular medicine
ISSN: 1757-4684
Titre abrégé: EMBO Mol Med
Pays: England
ID NLM: 101487380
Informations de publication
Date de publication:
02 Jan 2024
02 Jan 2024
Historique:
received:
05
01
2023
accepted:
07
12
2023
revised:
06
12
2023
medline:
5
1
2024
pubmed:
5
1
2024
entrez:
4
1
2024
Statut:
aheadofprint
Résumé
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.
Identifiants
pubmed: 38177539
doi: 10.1038/s44321-023-00017-7
pii: 10.1038/s44321-023-00017-7
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : EC | H2020 | PRIORITY 'Excellent science' | H2020 European Research Council (ERC)
ID : 874708
Organisme : Fondation pour la Recherche Médicale (FRM)
ID : R22108BB
Informations de copyright
© 2024. The Author(s).
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