Journal
MOLECULAR CELL
Volume 69, Issue 4, Pages 689-+Publisher
CELL PRESS
DOI: 10.1016/j.molcel.2018.01.010
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Funding
- NIH [Z01 HL005012-11, R01NS072241]
- Foundation Leducq [13CVD01]
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [ZICHL005904, ZIAHL005012, K08HL121174] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [T32DK007052] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE [R01NS072241] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE ON AGING [P30AG024827] Funding Source: NIH RePORTER
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Endothelial-to-mesenchymal transition (EndoMT) is a cellular process often initiated by the transforming growth factor beta (TGF-beta) 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(E-KO)) augments the magnitude of embryonic EndoMT, resulting in thickening of cardiac valves. Consistent with the known pathological effects of EndoMT, adult Cpt2(E-KO) 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.
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