Laboratory of Angiogenesis and Vascular Metabolism, Department of Oncology, KU Leuven, Leuven 3000, Belgium.
Laboratory of Angiogenesis and Vascular Metabolism, Center for Cancer Biology, VIB, KU Leuven, Campus Gasthuisberg O&N4, Herestraat 49-912, Leuven 3000, Belgium.
Open Biol. 2017 Dec;7(12). doi: 10.1098/rsob.170219.
Endothelial cell (EC) metabolism has lately emerged as a novel and promising therapeutic target to block vascular dysregulation associated with diseases like cancer and blinding eye disease. Glycolysis, fatty acid oxidation (FAO) and, more recently, glutamine/asparagine metabolism emerged as key regulators of EC metabolism, able to impact angiogenesis in health and disease. ECs are highly glycolytic as they require ATP and biomass for vessel sprouting. Notably, a regulator of the glycolytic pathway, 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3, controls vessel sprouting during the angiogenic switch and its inhibition in tumour ECs leads to vessel normalization, thereby reducing metastasis and ameliorating chemotherapy. Moreover, FAO promotes EC proliferation through DNA synthesis, and plays an essential role in lymphangiogenesis via epigenetic regulation of histone acetylation. Pathological angiogenesis was decreased upon blockade of carnitine palmitoyltransferase 1, a regulator of FAO in ECs. More recently, metabolism of glutamine, in conjunction with asparagine, was reported to maintain EC sprouting through TCA anaplerosis, redox homeostasis, mTOR activation and endoplasmic stress control. Inactivation or blockade of glutaminase 1, which hydrolyses glutamine into ammonia and glutamate, impairs angiogenesis in health and disease, while silencing of asparagine synthetase reduces vessel sprouting In this review, we summarize recent insights into EC metabolism and discuss therapeutic implications of targeting EC metabolism.
内皮细胞（EC）代谢最近已成为一种新颖而有前途的治疗靶点，可以阻断与癌症和致盲眼病等疾病相关的血管失调。糖酵解、脂肪酸氧化（FAO），以及最近的谷氨酰胺/天冬酰胺代谢，已成为 EC 代谢的关键调节剂，能够影响健康和疾病中的血管生成。EC 是高度糖酵解的，因为它们需要 ATP 和生物质来促进血管发芽。值得注意的是，糖酵解途径的调节剂 6-磷酸果糖-2-激酶/果糖-2,6-二磷酸酶 3，在血管生成开关期间控制血管发芽，其在肿瘤 EC 中的抑制作用导致血管正常化，从而减少转移并改善化疗。此外，FAO 通过 DNA 合成促进 EC 增殖，并通过组蛋白乙酰化的表观遗传调控在淋巴管生成中发挥重要作用。阻断肉碱棕榈酰转移酶 1（EC 中 FAO 的调节剂）可减少病理性血管生成。最近，有报道称，谷氨酰胺与天冬酰胺的代谢通过 TCA 回补、氧化还原稳态、mTOR 激活和内质网应激控制来维持 EC 发芽。谷氨酰胺酶 1 的失活或阻断（将谷氨酰胺水解为氨和谷氨酸）会损害健康和疾病中的血管生成，而天冬酰胺合成酶的沉默则会减少血管发芽。在这篇综述中，我们总结了 EC 代谢的最新见解，并讨论了针对 EC 代谢的治疗意义。
