淋巴系统
医学
阿佩林
纤维化
淋巴管新生
淋巴水肿
淋巴管
病理
内科学
受体
癌症
乳腺癌
转移
作者
Asalaa Lamaa,Justine Creff,Emeline Benuzzi,Françoise Pujol,Tangra Draia-Nicolau,Manon Nougué,Lena Verdu,Florent Morfoisse,Éric Lacazette,Philippe Valet,Benoît Chaput,Fabian Gross,Régis Gayon,Pascale Bouillé,Julie Malloizel‐Delaunay,A. Bura-Rivière,Anne-Catherine Prats,Barbara Garmy‐Susini
标识
DOI:10.1101/2023.01.05.522869
摘要
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 lymphedematous arm compared to 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 safe and non-integrative RNA-delivery LentiFlash ® vector that will be evaluated for phase I/IIa clinical trial.
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