Endothelial PFKFB3 Plays a Critical Role in Angiogenesis

Abstract

Objective 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. Approach and Results 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. Conclusions 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.

Targeting of MCT1 and PFKFB3 influences cell proliferation and apoptosis in bladder cancer by altering the tumor microenvironment

“…Meanwhile, research indicates that blood vessel growth is inhibited by blocking glycolysis and removing the energy source of vascular ECs. Targeting PFKFB3 can effectively reduce the motility, proliferation, invasion and angiogenesis of ECs (24). In the present study, the apoptosis rate of the HUVECs was significantly increased after silencing of MCT1 or/and PFKFB3 (Fig.…”

Glycolytic Reprogramming in Myofibroblast Differentiation and Lung Fibrosis

“…More importantly, TGF-b1-induced myo-Fb differentiation was also inhibited when PFKFB3 was knocked down ( Figure 4B). To further characterize the role of the augmented glycolysis in myo-Fb differentiation, we used a well-defined PFKFB3 inhibitor 3PO to suppress glycolysis (31,36). As shown in Figure 4C, 3PO dampened glycolysis in TGFb1-induced myo-Fbs.…”

Kinome Screen Identifies PFKFB3 and Glucose Metabolism as Important Regulators of the Insulin/Insulin-like Growth Factor (IGF)-1 Signaling Pathway

“…To further characterize this kinase in 3T3-L1 adipocytes, we employed 3-PO, a competitive inhibitor of PFKFB3 that binds to the substrate binding site in PFKFB3 (53). 3-PO is specific for PFKFB3 as verified in cells with reduced PFKFB3 (53,54), and it has been widely used to inhibit PFKFB3 in vitro and in vivo (53)(54)(55)(56)(57)(58)(59). In 3T3-L1 adipocytes, insulin significantly increased the levels of Fru-2,6-BP, the product of PFKFB3 activity, by 1.7-fold and incubation of cells with 3-PO blocked this increase, thus confirming that 3-PO inhibited PFKFB3 (Fig.…”