Cell Death Research and Therapy Group, Department of Cellular and Molecular Medicine, KU Leuven, Herestraat 49, 3000, Leuven, Belgium.
VIB Center for Cancer Biology Research, 3000, Leuven, Belgium.
Nat Commun. 2022 May 19;13(1):2760. doi: 10.1038/s41467-022-30490-6.
Autophagy has vasculoprotective roles, but whether and how it regulates lymphatic endothelial cells (LEC) homeostasis and lymphangiogenesis is unknown. Here, we show that genetic deficiency of autophagy in LEC impairs responses to VEGF-C and injury-driven corneal lymphangiogenesis. Autophagy loss in LEC compromises the expression of main effectors of LEC identity, like VEGFR3, affects mitochondrial dynamics and causes an accumulation of lipid droplets (LDs) in vitro and in vivo. When lipophagy is impaired, mitochondrial ATP production, fatty acid oxidation, acetyl-CoA/CoA ratio and expression of lymphangiogenic PROX1 target genes are dwindled. Enforcing mitochondria fusion by silencing dynamin-related-protein 1 (DRP1) in autophagy-deficient LEC fails to restore LDs turnover and lymphatic gene expression, whereas supplementing the fatty acid precursor acetate rescues VEGFR3 levels and signaling, and lymphangiogenesis in LEC-Atg5 mice. Our findings reveal that lipophagy in LEC by supporting FAO, preserves a mitochondrial-PROX1 gene expression circuit that safeguards LEC responsiveness to lymphangiogenic mediators and lymphangiogenesis.
自噬具有血管保护作用，但它是否以及如何调节淋巴管内皮细胞（LEC）的稳态和淋巴管生成尚不清楚。在这里，我们表明 LEC 中的自噬基因缺失会损害对 VEGF-C 和损伤驱动的角膜淋巴管生成的反应。LEC 中的自噬丧失会损害 LEC 身份的主要效应子的表达，如 VEGFR3，影响线粒体动力学，并导致体外和体内脂滴（LDs）的积累。当脂噬作用受损时，线粒体 ATP 产生、脂肪酸氧化、乙酰辅酶 A/辅酶 A 比和淋巴管生成 PROX1 靶基因的表达减少。通过沉默自噬缺陷的 LEC 中的 dynamin-related-protein 1 (DRP1) 来强制线粒体融合，无法恢复 LDs 的周转和淋巴管基因表达，而补充脂肪酸前体乙酸盐可挽救 LEC-Atg5 小鼠中 VEGFR3 水平和信号转导以及淋巴管生成。我们的研究结果表明，LEC 中的脂噬作用通过支持 FAO，维持了一个线粒体-PROX1 基因表达回路，该回路可保护 LEC 对淋巴管生成介质和淋巴管生成的反应性。
