Fatty acid carbon is essential for dNTP synthesis in endothelial cells.
Fatty acid carbon is essential for dNTP synthesis in endothelial cells.
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DOI：
10.1038/nature14362
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发表时间：
2015-04-09
期刊：
影响因子：
64.8
通讯作者：
Carmeliet, Peter
中科院分区：
文献类型：
--
作者：
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;Godde, Lucica;Vinckier, Stefan;Van Veldhoven, Paul P.;Eelen, Guy;Schoonjans, Luc;Gerhardt, Holger;Dewerchin, Mieke;Baes, Myriam;De Bock, Katrien;Ghesquiere, Bart;Lunt, Sophia Y.;Fendt, Sarah-Maria;Carmeliet, Peter
内皮细胞（ECs）在血管发芽过程中的代谢研究仍然很少。在这里，我们报道了CPT1a（脂肪酸氧化（FAO）的限速酶）的内皮缺失，由于内皮细胞增殖受损而不是迁移，导致血管发芽缺陷。ECs中FAO的减少不会导致能量消耗或破坏氧化还原稳态，但会损害DNA复制的从头核苷酸合成。对照ec的同位素标记研究表明，脂肪酸碳大量补充了克雷布斯循环，并被纳入天冬氨酸（核苷酸前体）、单磷酸尿苷（三磷酸嘧啶核苷前体）和DNA中。CPT1a沉默减少了这些过程，并减少了EC中天冬氨酸和脱氧核糖核苷三磷酸的储存。乙酸（代谢为乙酰辅酶a，从而取代了耗尽的fao衍生的乙酰辅酶a）或核苷混合物挽救了cpt1a沉默的ec的表型。最后，CPT1阻断可抑制病理性眼部血管生成，提示阻断血管生成的新策略。
The metabolism of endothelial cells (ECs) during vessel sprouting remains poorly studied. Here, we report that endothelial loss of CPT1a, a rate-limiting enzyme of fatty acid oxidation (FAO), caused vascular sprouting defects due to impaired proliferation, not migration of ECs. Reduction of FAO in ECs did not cause energy depletion or disturb redox homeostasis, but impaired de novo nucleotide synthesis for DNA replication. Isotope labeling studies in control ECs 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 EC 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 ECs. Finally, CPT1 blockade inhibited pathological ocular angiogenesis, suggesting a novel strategy for blocking angiogenesis.
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影响因子：
64.5
作者：
Sakaue-Sawano, Asako;Kurokawa, Hiroshi;Miyawaki, Atsushi
通讯作者：
Miyawaki, Atsushi
影响因子：
82.9
作者：
Carmeliet, P;Moons, L;Persico, MG
通讯作者：
Persico, MG
影响因子：
64.5
作者：
De Bock, Katrien;Georgiadou, Maria;Carmeliet, Peter
通讯作者：
Carmeliet, Peter
影响因子：
3.9
作者：
Scott, A.;Fruttiger, M.
通讯作者：
Fruttiger, M.
影响因子：
15.9
作者：
JAFFE, EA;NACHMAN, RL;MINICK, CR
通讯作者：
MINICK, CR