A Metabolic Basis for Endothelial-to-Mesenchymal Transition.

Xiong J, Kawagishi H, Yan Y, Liu J, Wells QS, Edmunds LR, Fergusson MM, Yu ZX, Rovira II, Brittain EL, Wolfgang MJ, Jurczak MJ, Fessel JP, Finkel T
Mol Cell. 2018 69 (4): 689-698.e7

PMID: 29429925 · PMCID: PMC5816688 · DOI:10.1016/j.molcel.2018.01.010

Endothelial-to-mesenchymal transition (EndoMT) is a cellular process often initiated by the transforming growth factor β (TGF-β) family of ligands. Although required for normal heart valve development, deregulated EndoMT is linked to a wide range of pathological conditions. Here, we demonstrate that endothelial fatty acid oxidation (FAO) is a critical in vitro and in vivo regulator of EndoMT. We further show that this FAO-dependent metabolic regulation of EndoMT occurs through alterations in intracellular acetyl-CoA levels. Disruption of FAO via conditional deletion of endothelial carnitine palmitoyltransferase II (Cpt2) augments the magnitude of embryonic EndoMT, resulting in thickening of cardiac valves. Consistent with the known pathological effects of EndoMT, adult Cpt2 mice demonstrate increased permeability in multiple vascular beds. Taken together, these results demonstrate that endothelial FAO is required to maintain endothelial cell fate and that therapeutic manipulation of endothelial metabolism could provide the basis for treating a growing number of EndoMT-linked pathological conditions.

Copyright © 2018 Elsevier Inc. All rights reserved.

MeSH Terms (20)

3-Hydroxyacyl CoA Dehydrogenases Acetyl-CoA C-Acyltransferase Acetyl Coenzyme A Animals Carbon-Carbon Double Bond Isomerases Carnitine O-Palmitoyltransferase Cells, Cultured Endothelium, Vascular Enoyl-CoA Hydratase Epithelial-Mesenchymal Transition Fatty Acids Female Male Mice Mice, Inbred C57BL Mice, Knockout Oxidation-Reduction Racemases and Epimerases Signal Transduction Transforming Growth Factor beta

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