| Autor: |
Odeta Mece, Diede Houbaert, Tania Durré, Hannelore Maes, Marco Schaaf, Sanket More, Maarten Ganne, Melissa García-Caballero, Mila Borri, Jelle Verhoeven, Silvia Blacher, Bart Ghesquière, Mieke Dewerchin, Johannes Swinnen, Stefan Vinckier, Maria Soengas, Peter Carmeliet, Agnès Noel, Patrizia Agostinis |
| Rok vydání: |
2021 |
| Předmět: |
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| Popis: |
Autophagy has an emerging vasculoprotective role but whether and how it regulates lymphatic endothelial cells (LEC) and lymphangiogenesis is unknown. Here, we show that genetic deficiency of autophagy in LEC impairs the responses to VEGF-C and injury-driven corneal lymphangiogenesis. Loss of autophagy compromises expression of lymphatic markers, affects mitochondrial dynamics and causes an accumulation of lipid droplets (LDs) in LEC and lymphatic vessels in vivo. When LDs accumulate because lipophagy is impaired, mitochondrial ATP production, fatty acid oxidation (FAO), 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 affect LDs turnover and lymphatic gene expression, whereas supplementing the acetyl-CoA precursor acetate rescues LEC identity and lymphangiogenesis in LEC-Atg5-/- mice. Our findings reveal that lipophagy in LEC by supporting FAO, preserves a mitochondrial-PROX1 gene expression circuit that ensures LEC identity, responsiveness to lymphangiogenic mediators and lymphangiogenesis. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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