title: Partial and transient reduction of glycolysis by PFKFB3 blockade reduces pathological angiogenesis.
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.
authors: Laboratory of Angiogenesis and Neurovascular link, Vesalius Research Center, Department of Oncology, University of Leuven, Leuven 3000, Belgium; Laboratory of Angiogenesis and Neurovascular link, Vesalius Research Center, VIB, Leuven 3000, Belgium.
authors: Sandra
authors: S
authors: Schoors
authors: Laboratory of Angiogenesis and Neurovascular link, Vesalius Research Center, Department of Oncology, University of Leuven, Leuven 3000, Belgium; Laboratory of Angiogenesis and Neurovascular link, Vesalius Research Center, VIB, Leuven 3000, Belgium.
authors: Katrien
authors: K
authors: De Bock
authors: Laboratory of Angiogenesis and Neurovascular link, Vesalius Research Center, Department of Oncology, University of Leuven, Leuven 3000, Belgium; Laboratory of Angiogenesis and Neurovascular link, Vesalius Research Center, VIB, Leuven 3000, Belgium.
authors: Anna Rita
authors: AR
authors: Cantelmo
authors: Laboratory of Angiogenesis and Neurovascular link, Vesalius Research Center, Department of Oncology, University of Leuven, Leuven 3000, Belgium; Laboratory of Angiogenesis and Neurovascular link, Vesalius Research Center, VIB, Leuven 3000, Belgium.
authors: Maria
authors: M
authors: Georgiadou
authors: Laboratory of Angiogenesis and Neurovascular link, Vesalius Research Center, Department of Oncology, University of Leuven, Leuven 3000, Belgium; Laboratory of Angiogenesis and Neurovascular link, Vesalius Research Center, VIB, Leuven 3000, Belgium.
authors: Bart
authors: B
authors: Ghesquière
authors: Laboratory of Angiogenesis and Neurovascular link, Vesalius Research Center, Department of Oncology, University of Leuven, Leuven 3000, Belgium; Laboratory of Angiogenesis and Neurovascular link, Vesalius Research Center, VIB, Leuven 3000, Belgium.
authors: Sandra
authors: S
authors: Cauwenberghs
authors: Laboratory of Angiogenesis and Neurovascular link, Vesalius Research Center, Department of Oncology, University of Leuven, Leuven 3000, Belgium; Laboratory of Angiogenesis and Neurovascular link, Vesalius Research Center, VIB, Leuven 3000, Belgium.
authors: Anna
authors: A
authors: Kuchnio
authors: Laboratory of Angiogenesis and Neurovascular link, Vesalius Research Center, Department of Oncology, University of Leuven, Leuven 3000, Belgium; Laboratory of Angiogenesis and Neurovascular link, Vesalius Research Center, VIB, Leuven 3000, Belgium.
authors: Brian W
authors: BW
authors: Wong
authors: Laboratory of Angiogenesis and Neurovascular link, Vesalius Research Center, Department of Oncology, University of Leuven, Leuven 3000, Belgium; Laboratory of Angiogenesis and Neurovascular link, Vesalius Research Center, VIB, Leuven 3000, Belgium.
authors: Annelies
authors: A
authors: Quaegebeur
authors: Laboratory of Angiogenesis and Neurovascular link, Vesalius Research Center, Department of Oncology, University of Leuven, Leuven 3000, Belgium; Laboratory of Angiogenesis and Neurovascular link, Vesalius Research Center, VIB, Leuven 3000, Belgium.
authors: Jermaine
authors: J
authors: Goveia
authors: Laboratory of Angiogenesis and Neurovascular link, Vesalius Research Center, Department of Oncology, University of Leuven, Leuven 3000, Belgium; Laboratory of Angiogenesis and Neurovascular link, Vesalius Research Center, VIB, Leuven 3000, Belgium.
authors: Francesco
authors: F
authors: Bifari
authors: Laboratory of Angiogenesis and Neurovascular link, Vesalius Research Center, Department of Oncology, University of Leuven, Leuven 3000, Belgium; Laboratory of Angiogenesis and Neurovascular link, Vesalius Research Center, VIB, Leuven 3000, Belgium.
authors: Xingwu
authors: X
authors: Wang
authors: Vascular Biology Laboratory, London Research Institute, Cancer Research UK, London WC2A 3LY, UK.
authors: Raquel
authors: R
authors: Blanco
authors: Laboratory of Angiogenesis and Neurovascular link, Vesalius Research Center, Department of Oncology, University of Leuven, Leuven 3000, Belgium; Laboratory of Angiogenesis and Neurovascular link, Vesalius Research Center, VIB, Leuven 3000, Belgium.
authors: Bieke
authors: B
authors: Tembuyser
authors: Laboratory of Angiogenesis and Neurovascular link, Vesalius Research Center, Department of Oncology, University of Leuven, Leuven 3000, Belgium; Laboratory of Angiogenesis and Neurovascular link, Vesalius Research Center, VIB, Leuven 3000, Belgium.
authors: Ivo
authors: I
authors: Cornelissen
authors: Laboratory of Angiogenesis and Neurovascular link, Vesalius Research Center, Department of Oncology, University of Leuven, Leuven 3000, Belgium; Laboratory of Angiogenesis and Neurovascular link, Vesalius Research Center, VIB, Leuven 3000, Belgium.
authors: Ann
authors: A
authors: Bouché
authors: Laboratory of Angiogenesis and Neurovascular link, Vesalius Research Center, Department of Oncology, University of Leuven, Leuven 3000, Belgium; Laboratory of Angiogenesis and Neurovascular link, Vesalius Research Center, VIB, Leuven 3000, Belgium.
authors: Stefan
authors: S
authors: Vinckier
authors: Department of Biochemistry and Molecular Biology and IBUB, Universitat de Barcelona, Barcelona 08007, Spain.
authors: Santiago
authors: S
authors: Diaz-Moralli
authors: Vascular Biology Laboratory, London Research Institute, Cancer Research UK, London WC2A 3LY, UK; Vascular Patterning Laboratory, Vesalius Research Center, University of Leuven, Leuven 3000, Belgium; Vascular Patterning Laboratory, Vesalius Research Center, VIB, Leuven 3000, Belgium.
authors: Holger
authors: H
authors: Gerhardt
authors: James Graham Brown Cancer Center, University of Louisville, Louisville, KY 40202, USA.
authors: Sucheta
authors: S
authors: Telang
authors: Department of Biochemistry and Molecular Biology and IBUB, Universitat de Barcelona, Barcelona 08007, Spain.
authors: Marta
authors: M
authors: Cascante
authors: James Graham Brown Cancer Center, University of Louisville, Louisville, KY 40202, USA.
authors: Jason
authors: J
authors: Chesney
authors: Laboratory of Angiogenesis and Neurovascular link, Vesalius Research Center, Department of Oncology, University of Leuven, Leuven 3000, Belgium; Laboratory of Angiogenesis and Neurovascular link, Vesalius Research Center, VIB, Leuven 3000, Belgium.
authors: Mieke
authors: M
authors: Dewerchin
authors: Laboratory of Angiogenesis and Neurovascular link, Vesalius Research Center, Department of Oncology, University of Leuven, Leuven 3000, Belgium; Laboratory of Angiogenesis and Neurovascular link, Vesalius Research Center, VIB, Leuven 3000, Belgium. Electronic address: peter.carmeliet@vib-kuleuven.be.
authors: Peter
authors: P
authors: Carmeliet
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D000818:Animals; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects; D006019:Glycolysis / Q000187:drug effects; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D009389:Neovascularization, Pathologic / Q000201:enzymology* / Q000235:genetics; D018919:Neovascularization, Physiologic / Q000187:drug effects / Q000235:genetics; D025481:Phosphofructokinase-2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D012171:Retinal Vessels / Q000187:drug effects / Q000254:growth & development / Q000473:pathology; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D015027:Zebrafish
chemical_list: C527590:3-(3-pyridinyl)-1-(4-pyridinyl)-2-propen-1-one; D020533:Angiogenesis Inhibitors; D011725:Pyridines; D025481:Phosphofructokinase-2; D040281:Vascular Endothelial Growth Factor Receptor-1