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Partial and transient reduction of glycolysis by PFKFB3 blockade reduces pathological angiogenesis

Item Type:Article
Title:Partial and transient reduction of glycolysis by PFKFB3 blockade reduces pathological angiogenesis
Creators Name:Schoors, S. and De Bock, K. and Cantelmo, A.R. and Georgiadou, M. and Ghesquière, B. and Cauwenberghs, S. and Kuchnio, A. and Wong, B.W. and Quaegebeur, A. and Goveia, J. and Bifari, F. and Wang, X. and Blanco, R. and Tembuyser, B. and Cornelissen, I. and Bouché, A. and Vinckier, S. and Diaz-Moralli, S. and Gerhardt, H. and Telang, S. and Cascante, M. and Chesney, J. and Dewerchin, M. and Carmeliet, P.
Abstract: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.
Keywords:Angiogenesis Inhibitors, Animal Disease Models, Cell Movement, Cell Proliferation, Glycolysis, Gene Expression Regulation, Human Umbilical Vein Endothelial Cells, Pathologic Neovascularization, Phosphofructokinase-2, Physiologic Neovascularization, Pyridines, Retinal Vessels, Vascular Endothelial Growth Factor Receptor-1, Animals, Mice, Zebrafish
Source:Cell Metabolism
ISSN:1550-4131
Publisher:Cell Press (U.S.A.)
Volume:19
Number:1
Page Range:37-48
Date:7 January 2014
Official Publication:https://doi.org/10.1016/j.cmet.2013.11.008
PubMed:View item in PubMed

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