Fatty Acids; Transcription Factors; Animals; Autophagy/genetics; Endothelial Cells/metabolism; Fatty Acids/metabolism; Lipid Droplets/metabolism; Mice; Mitochondria; Transcription Factors/metabolism; Lymphangiogenesis/genetics; Lymphatic Vessels/metabolism; Autophagy; Endothelial Cells; Lipid Droplets; Lymphangiogenesis; Lymphatic Vessels; Chemistry (all); Biochemistry, Genetics and Molecular Biology (all); Multidisciplinary; Physics and Astronomy (all); General Physics and Astronomy; General Biochemistry, Genetics and Molecular Biology; General Chemistry
Abstract :
[en] 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.
Disciplines :
Oncology
Author, co-author :
Meçe, Odeta; 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
Houbaert, Diede ; 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
Sassano, Maria-Livia ; 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
Durré, Tania; Laboratory of Tumor and Development Biology, GIGA (GIGA-Cancer), Liege University, B23, Avenue Hippocrate 13, 4000, Liege, Belgium
Maes, Hannelore ; Université de Liège - ULiège ; Cell Death Research and Therapy Group, Department of Cellular and Molecular Medicine, KU Leuven, Herestraat 49, 3000, Leuven, Belgium
Schaaf, Marco; 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
More, Sanket; 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
Ganne, Maarten; 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
García-Caballero, Melissa; Laboratory of Angiogenesis and Vascular Metabolism, VIB Center for Cancer Biology, VIB, Leuven, Belgium ; Laboratory of Angiogenesis and Vascular Metabolism, Department of Oncology, Leuven Cancer Institute, KU Leuven, Leuven, Belgium
Borri, Mila; Laboratory of Angiogenesis and Vascular Metabolism, VIB Center for Cancer Biology, VIB, Leuven, Belgium ; Laboratory of Angiogenesis and Vascular Metabolism, Department of Oncology, Leuven Cancer Institute, KU Leuven, Leuven, Belgium
Verhoeven, Jelle; 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
Agrawal, Madhur; 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
Jacobs, Kathryn ; Cell Death Research and Therapy Group, Department of Cellular and Molecular Medicine, KU Leuven, Herestraat 49, 3000, Leuven, Belgium ; Laboratory for Tumor Microenvironment and Therapeutic Resistance, Department of Oncology, KU Leuven, Leuven, Belgium ; Laboratory for Tumor Microenvironment and Therapeutic Resistance VIB Center for Cancer Biology, VIB, Leuven, Belgium
Bergers, Gabriele; Laboratory for Tumor Microenvironment and Therapeutic Resistance, Department of Oncology, KU Leuven, Leuven, Belgium ; Laboratory for Tumor Microenvironment and Therapeutic Resistance VIB Center for Cancer Biology, VIB, Leuven, Belgium
Blacher, Silvia ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Biologie cellulaire et moléculaire
Ghesquière, Bart ; Metabolomics Expertise Center, Department of Oncology, KU Leuven, Leuven, Belgium
Dewerchin, Mieke ; Laboratory of Angiogenesis and Vascular Metabolism, VIB Center for Cancer Biology, VIB, Leuven, Belgium ; Laboratory of Angiogenesis and Vascular Metabolism, Department of Oncology, Leuven Cancer Institute, KU Leuven, Leuven, Belgium
Swinnen, Johan V ; Laboratory of Lipid Metabolism and Cancer, Department of Oncology, KU Leuven, Leuven, Belgium
Vinckier, Stefan; Laboratory of Angiogenesis and Vascular Metabolism, VIB Center for Cancer Biology, VIB, Leuven, Belgium ; Laboratory of Angiogenesis and Vascular Metabolism, Department of Oncology, Leuven Cancer Institute, KU Leuven, Leuven, Belgium
Soengas, María S ; Melanoma Laboratory, Molecular Oncology Programme, Spanish National Cancer Research Centre (CNIO), Madrid, 28029, Spain
Carmeliet, Peter ; Laboratory of Angiogenesis and Vascular Metabolism, VIB Center for Cancer Biology, VIB, Leuven, Belgium ; Laboratory of Angiogenesis and Vascular Metabolism, Department of Oncology, Leuven Cancer Institute, KU Leuven, Leuven, Belgium
Noël, Agnès ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Biologie cellulaire et moléculaire
Agostinis, Patrizia ; Cell Death Research and Therapy Group, Department of Cellular and Molecular Medicine, KU Leuven, Herestraat 49, 3000, Leuven, Belgium. patrizia.agostinis@kuleuven.be ; VIB Center for Cancer Biology Research, 3000, Leuven, Belgium. patrizia.agostinis@kuleuven.be
We thank K. Rillaerts, J. Souffreau, and A. Bouché, for expert technical support and Dr. A. Luttun and Dr. A. Zijsen for sharing tools and advices. P.A. is supported by grants from the Flemish Research Foundation (FWO-Vlaanderen; G076617N, G049817N, G070115N), the EOS MetaNiche consortium N° 40007532, Stichting tegen Kanker (FAF-F/2018/1252) and the iBOF/21/053 ATLANTIS consortium with G.B. D.H. is the recipient of an FWO Doctoral Fellowship from the Flemish Research Foundation (FWO-Vlaanderen, 1186019N), Belgium. M.B. is supported by the ‘Fonds voor Wetenschappelijk Onderzoek’ (FWO). K.J. is the recipient of an FWO Postdoctoral Fellowship from the Flemish Research Foundation (FWO-Vlaanderen). P.C. is supported by Methusalem funding by the Flemish government, and by an ERC Advanced Research Grant (EU-ERC269073).
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