Endothelial PFKFB3 plays a critical role in angiogenesis.
Endothelial PFKFB3 plays a critical role in angiogenesis.
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内皮PFKFB3在血管生成中起关键作用。
DOI：
10.1161/atvbaha.113.303041
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发表时间：
2014-06
期刊：
影响因子：
--
通讯作者：
Huo Y
中科院分区：
文献类型：
--
作者：
Xu Y;An X;Guo X;Habtetsion TG;Wang Y;Xu X;Kandala S;Li Q;Li H;Zhang C;Caldwell RB;Fulton DJ;Su Y;Hoda MN;Zhou G;Wu C;Huo Y
血管细胞，特别是内皮细胞，通过有氧糖酵解产生能量来支持细胞功能。内皮糖酵解对血管生成的影响尚不清楚。6-磷酸果糖-2-激酶/果糖-2，6-二磷酸酶亚型3（PFKFB 3）是内皮糖酵解的关键酶。通过阻断或缺失内皮细胞中的PFKFB 3，我们研究了内皮糖酵解对体外和体内血管生成的影响。在缺氧条件下或血管生成因子治疗后，内皮PFKFB 3在体外和体内均上调。在体外，PFKFB 3的敲低或过表达分别抑制或加速内皮细胞增殖和迁移。当内皮细胞PFKFB 3基因缺失或用PFKFB 3抑制剂治疗时，来自氧诱导视网膜病变模型的新生小鼠显示出视网膜中新生血管生长受到抑制。此外，植入缺乏内皮PFKFB 3的小鼠中的肿瘤生长更慢，并且提供更少的血流量。在PFKFB 3敲低的内皮细胞中观察到较低水平的磷酸化AKT（pAKT），这伴随着细胞内乳酸的减少。向PFKFB 3敲除细胞中加入乳酸盐可挽救内皮细胞增殖和迁移的抑制。内皮PFKFB 3的阻断或缺失在体外和体内均降低血管生成。因此，PFKFB 3是减少内皮糖酵解及其相关病理性血管生成的有希望的靶点。
Vascular cells, particularly endothelial cells, adopt aerobic glycolysis to generate energy to support cellular functions. The effect of endothelial glycolysis on angiogenesis remains unclear. 6-Phosphofructo-2-kinase/fructose-2, 6-bisphosphatase, isoform 3 (PFKFB3), is a critical enzyme for endothelial glycolysis. By blocking or deleting PFKFB3 in endothelial cells, we investigated the influence of endothelial glycolysis on angiogenesis both in vitro and in vivo. Under hypoxic conditions or following treatment with angiogenic factors, endothelial PFKFB3 was upregulated both in vitro and in vivo. The knockdown or overexpression of PFKFB3 suppressed or accelerated endothelial proliferation and migration in vitro, respectively. Neonatal mice from a model of oxygen-induced retinopathy showed suppressed neovascular growth in the retina when endothelial PFKFB3 was genetically deleted or when the mice were treated with a PFKFB3 inhibitor. Additionally, tumors implanted in mice deficient in endothelial PFKFB3 grew more slowly and were provided with less blood flow. A lower level of phosphorylated AKT (pAKT) was observed in PFKFB3-knockdown endothelial cells, which was accompanied by a decrease in intracellular lactate. The addition of lactate to PFKFB3-knockdown cells rescued the suppression of endothelial proliferation and migration. The blockade or deletion of endothelial PFKFB3 decreases angiogenesis both in vitro and in vivo. Thus, PFKFB3 is a promising target for the reduction of endothelial glycolysis and its related pathological angiogenesis.