LAUSR

ABSTRACT Lymphatic endothelial cells (LECs) exploit fatty acid oxidation (FAO) to grow and to maintain lymphatic vessel identity through the epigenetic regulation of the essential transcription factor PROX1. In our recent study, we found that LEC-specific loss of ATG5 prevents injury-induced lymphangiogenesis in vivo. Inadequate degradation of lipid droplets (LDs) caused by genetic ablation of ATG5 in LECs disturbs mitochondrial fitness, and reduces mitochondrial FAO and acetyl-CoA levels, ultimately affecting PROX1-mediated epigenetic regulation of CPT1A and key lymphatic markers, most importantly FLT4/VEGFR3. Supplementing the fatty acid precursor acetate rescues defective inflammation-driven lymphangiogenesis in LEC-specific atg5 knockout mice. Thus, efficient macroautophagy/autophagy-mediated LD breakdown is critical to maintain mitochondrial metabolism and acetyl-CoA levels, which sustain a PROX1-mediated lymphatic gene program required for LEC identity and inflammation-driven lymphangiogenesis.