Partial and Transient Reduction of Glycolysis by PFKFB3 Blockade Reduces Pathological Angiogenesis
- Authors
- Schoors, S., De Bock, K., Cantelmo, A.R., Georgiadou, M., Ghesquière, B., Cauwenberghs, S., Kuchnio, A., Wong, B.W., Quaegebeur, A., Goveia, J., Bifari, F., Wang, X., Blanco, R., Tembuyser, B., Cornelissen, I., Bouché, A., Vinckier, S., Diaz-Moralli, S., Gerhardt, H., Telang, S., Cascante, M., Chesney, J., Dewerchin, M., and Carmeliet, P.
- ID
- ZDB-PUB-140210-24
- Date
- 2014
- Source
- Cell Metabolism 19(1): 37-48 (Journal)
- Registered Authors
- Keywords
- none
- MeSH Terms
-
- Angiogenesis Inhibitors/pharmacology
- Animals
- Cell Movement/drug effects
- Cell Proliferation/drug effects
- Disease Models, Animal
- Gene Expression Regulation/drug effects
- Glycolysis*/drug effects
- Human Umbilical Vein Endothelial Cells/drug effects
- Human Umbilical Vein Endothelial Cells/enzymology
- Human Umbilical Vein Endothelial Cells/pathology
- Humans
- Mice
- Mice, Inbred C57BL
- Neovascularization, Pathologic/enzymology*
- Neovascularization, Pathologic/genetics
- Neovascularization, Physiologic/drug effects
- Neovascularization, Physiologic/genetics
- Phosphofructokinase-2/antagonists & inhibitors*
- Phosphofructokinase-2/metabolism
- Pyridines/pharmacology
- Retinal Vessels/drug effects
- Retinal Vessels/growth & development
- Retinal Vessels/pathology
- Vascular Endothelial Growth Factor Receptor-1/antagonists & inhibitors
- Vascular Endothelial Growth Factor Receptor-1/metabolism
- Zebrafish
- PubMed
- 24332967 Full text @ Cell Metab.
Strategies targeting pathological angiogenesis have focused primarily on blocking vascular endothelial growth factor (VEGF), but resistance and insufficient efficacy limit their success, mandating alternative antiangiogenic strategies. We recently provided genetic evidence that the glycolytic activator phosphofructokinase-2/fructose-2,6-bisphosphatase 3 (PFKFB3) promotes vessel formation but did not explore the antiangiogenic therapeutic potential of PFKFB3 blockade. Here, we show that blockade of PFKFB3 by the small molecule 3-(3-pyridinyl)-1-(4-pyridinyl)-2-propen-1-one (3PO) reduced vessel sprouting in endothelial cell (EC) spheroids, zebrafish embryos, and the postnatal mouse retina by inhibiting EC proliferation and migration. 3PO also suppressed vascular hyperbranching induced by inhibition of Notch or VEGF receptor 1 (VEGFR1) and amplified the antiangiogenic effect of VEGF blockade. Although 3PO reduced glycolysis only partially and transiently in vivo, this sufficed to decrease pathological neovascularization in ocular and inflammatory models. These insights may offer therapeutic antiangiogenic opportunities.