Abstract
The metabolism of endothelial cells during vessel sprouting remains poorly studied. Here we report that endothelial loss of CPT1A, a rate-limiting enzyme of fatty acid oxidation (FAO), causes vascular sprouting defects due to impaired proliferation, not migration, of human and murine endothelial cells. Reduction of FAO in endothelial cells did not cause energy depletion or disturb redox homeostasis, but impaired de novo nucleotide synthesis for DNA replication. Isotope labelling studies in control endothelial cells showed that fatty acid carbons substantially replenished the Krebs cycle, and were incorporated into aspartate (a nucleotide precursor), uridine monophosphate (a precursor of pyrimidine nucleoside triphosphates) and DNA. CPT1A silencing reduced these processes and depleted endothelial cell stores of aspartate and deoxyribonucleoside triphosphates. Acetate (metabolized to acetyl-CoA, thereby substituting for the depleted FAO-derived acetyl-CoA) or a nucleoside mix rescued the phenotype of CPT1A-silenced endothelial cells. Finally, CPT1 blockade inhibited pathological ocular angiogenesis in mice, suggesting a novel strategy for blocking angiogenesis.
| Language | English (US) |
|---|---|
| Pages | 192-197 |
| Number of pages | 6 |
| Journal | Nature |
| Volume | 520 |
| Issue number | 7546 |
| DOIs | |
| State | Published - Apr 9 2015 |
Profile
ASJC Scopus subject areas
- General
- Medicine(all)
Cite this
Fatty acid carbon is essential for dNTP synthesis in endothelial cells. / Schoors, Sandra; Bruning, Ulrike; Missiaen, Rindert; Queiroz, Karla C S; Borgers, Gitte; Elia, Ilaria; Zecchin, Annalisa; Cantelmo, Anna Rita; Christen, Stefan; Goveia, Jermaine; Heggermont, Ward; Goddé, Lucica; Vinckier, Stefan; Van Veldhoven, Paul P.; Eelen, Guy; Schoonjans, Luc; Gerhardt, Holger; Dewerchin, Mieke; Baes, Myriam; De Bock, Katrien; Ghesquière, Bart; Lunt, Sophia Y.; Fendt, Sarah Maria; Carmeliet, Peter.
In: Nature, Vol. 520, No. 7546, 09.04.2015, p. 192-197.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Fatty acid carbon is essential for dNTP synthesis in endothelial cells
AU - Schoors,Sandra
AU - Bruning,Ulrike
AU - Missiaen,Rindert
AU - Queiroz,Karla C S
AU - Borgers,Gitte
AU - Elia,Ilaria
AU - Zecchin,Annalisa
AU - Cantelmo,Anna Rita
AU - Christen,Stefan
AU - Goveia,Jermaine
AU - Heggermont,Ward
AU - Goddé,Lucica
AU - Vinckier,Stefan
AU - Van Veldhoven,Paul P.
AU - Eelen,Guy
AU - Schoonjans,Luc
AU - Gerhardt,Holger
AU - Dewerchin,Mieke
AU - Baes,Myriam
AU - De Bock,Katrien
AU - Ghesquière,Bart
AU - Lunt,Sophia Y.
AU - Fendt,Sarah Maria
AU - Carmeliet,Peter
PY - 2015/4/9
Y1 - 2015/4/9
N2 - The metabolism of endothelial cells during vessel sprouting remains poorly studied. Here we report that endothelial loss of CPT1A, a rate-limiting enzyme of fatty acid oxidation (FAO), causes vascular sprouting defects due to impaired proliferation, not migration, of human and murine endothelial cells. Reduction of FAO in endothelial cells did not cause energy depletion or disturb redox homeostasis, but impaired de novo nucleotide synthesis for DNA replication. Isotope labelling studies in control endothelial cells showed that fatty acid carbons substantially replenished the Krebs cycle, and were incorporated into aspartate (a nucleotide precursor), uridine monophosphate (a precursor of pyrimidine nucleoside triphosphates) and DNA. CPT1A silencing reduced these processes and depleted endothelial cell stores of aspartate and deoxyribonucleoside triphosphates. Acetate (metabolized to acetyl-CoA, thereby substituting for the depleted FAO-derived acetyl-CoA) or a nucleoside mix rescued the phenotype of CPT1A-silenced endothelial cells. Finally, CPT1 blockade inhibited pathological ocular angiogenesis in mice, suggesting a novel strategy for blocking angiogenesis.
AB - The metabolism of endothelial cells during vessel sprouting remains poorly studied. Here we report that endothelial loss of CPT1A, a rate-limiting enzyme of fatty acid oxidation (FAO), causes vascular sprouting defects due to impaired proliferation, not migration, of human and murine endothelial cells. Reduction of FAO in endothelial cells did not cause energy depletion or disturb redox homeostasis, but impaired de novo nucleotide synthesis for DNA replication. Isotope labelling studies in control endothelial cells showed that fatty acid carbons substantially replenished the Krebs cycle, and were incorporated into aspartate (a nucleotide precursor), uridine monophosphate (a precursor of pyrimidine nucleoside triphosphates) and DNA. CPT1A silencing reduced these processes and depleted endothelial cell stores of aspartate and deoxyribonucleoside triphosphates. Acetate (metabolized to acetyl-CoA, thereby substituting for the depleted FAO-derived acetyl-CoA) or a nucleoside mix rescued the phenotype of CPT1A-silenced endothelial cells. Finally, CPT1 blockade inhibited pathological ocular angiogenesis in mice, suggesting a novel strategy for blocking angiogenesis.
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UR - http://www.scopus.com/inward/citedby.url?scp=84927563455&partnerID=8YFLogxK
U2 - 10.1038/nature14362
DO - 10.1038/nature14362
M3 - Article
VL - 520
SP - 192
EP - 197
JO - Nature
T2 - Nature
JF - Nature
SN - 0028-0836
IS - 7546
ER -