From the Vascular Biology Center, Department of Cellular Biology and Anatomy (Y.X., X.A., X.X., S.K., R.B.C., D.J.F., Y.H.), Cancer Center, Department of Medicine (T.G.H., G.Z.), and Department of Pharmacology and Toxicology (Y.W., Y.S.), Medical College of Georgia and Departments of Medical Laboratory, Imaging and Radiologic Sciences, and Neurology (M.N.H.), Georgia Regents University, Augusta; Drug Discovery Center, Key Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School, Shenzhen, China (X.A., Q.L., Y.H.); Department of Nutrition and Food Science, Texas A&M University, College Station (X.G., H.L., C.W.); and Department of Pharmacology, Rush Medical College, Rush University, Chicago, IL (C.Z.).
Arterioscler Thromb Vasc Biol. 2014 Jun;34(6):1231-9. doi: 10.1161/ATVBAHA.113.303041. Epub 2014 Apr 3.
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 after 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. In addition, tumors implanted in mice deficient in endothelial PFKFB3 grew more slowly and were provided with less blood flow. A lower level of phosphorylated protein kinase B 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.
血管细胞，尤其是内皮细胞，通过有氧糖酵解来产生能量以支持细胞功能。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，异构体 3（PFKFB3）是内皮糖酵解的关键酶。通过阻断或删除内皮细胞中的 PFKFB3，我们研究了内皮糖酵解对体外和体内血管生成的影响。
在缺氧条件下或在接受血管生成因子治疗后，体外和体内的内皮 PFKFB3 均上调。PFKFB3 的敲低或过表达分别抑制或加速了内皮细胞的增殖和迁移。在氧诱导性视网膜病变模型的新生小鼠中，内皮 PFKFB3 基因缺失或给予 PFKFB3 抑制剂时，视网膜中的新生血管生长受到抑制。此外，内皮 PFKFB3 缺失的小鼠中的肿瘤生长更慢，并且提供的血流量更少。在 PFKFB3 敲低的内皮细胞中观察到磷酸化蛋白激酶 B 的水平降低，同时细胞内乳酸盐减少。向 PFKFB3 敲低细胞中添加乳酸盐可挽救内皮细胞增殖和迁移的抑制。
阻断或删除内皮 PFKFB3 可减少体外和体内的血管生成。因此，PFKFB3 是减少内皮糖酵解及其相关病理性血管生成的有前途的靶标。
