Partial and Transient Reduction of Glycolysis by PFKFB3 Blockade Reduces Pathological Angiogenesis

被引：435

作者：

Schoors, Sandra ^{[1
,2
]}

De Bock, Katrien ^{[1
,2
]}

Cantelmo, Anna Rita ^{[1
,2
]}

Georgiadou, Maria ^{[1
,2
]}

Ghesquiere, Bart ^{[1
,2
]}

Cauwenberghs, Sandra ^{[1
,2
]}

Kuchnio, Anna ^{[1
,2
]}

Wong, Brian W. ^{[1
,2
]}

Quaegebeur, Annelies ^{[1
,2
]}

Goveia, Jermaine ^{[1
,2
]}

Bifari, Francesco ^{[1
,2
]}

Wang, Xingwu ^{[1
,2
]}

Blanco, Raquel ^{[3
]}

Tembuyser, Bieke ^{[1
,2
]}

Cornelissen, Ivo ^{[1
,2
]}

Bouche, Ann ^{[1
,2
]}

Vinckier, Stefan ^{[1
,2
]}

Diaz-Moralli, Santiago ^{[4
,5
]}

Gerhardt, Holger ^{[3
,6
,7
]}

Telang, Sucheta ^{[8
]}

Cascante, Marta ^{[4
,5
]}

Chesney, Jason ^{[8
]}

Dewerchin, Mieke ^{[1
,2
]}

Carmeliet, Peter ^{[1
,2
]}

机构：

[1] Univ Leuven, Vesalius Res Ctr, Dept Oncol, Lab Angiogenesis & Neurovasc Link, B-3000 Louvain, Belgium

[2] VIB, Vesalius Res Ctr, Lab Angiogenesis & Neurovasc Link, B-3000 Louvain, Belgium

[3] Canc Res UK, London Res Inst, Vasc Biol Lab, London WC2A 3LY, England

[4] Univ Barcelona, Dept Biochem & Mol Biol, E-08007 Barcelona, Spain

[5] Univ Barcelona, IBUB, E-08007 Barcelona, Spain

[6] Univ Leuven, Vesalius Res Ctr, Vasc Patterning Lab, B-3000 Louvain, Belgium

[7] VIB, Vesalius Res Ctr, Vasc Patterning Lab, B-3000 Louvain, Belgium

[8] Univ Louisville, James Graham Brown Canc Ctr, Louisville, KY 40202 USA

来源：

CELL METABOLISM | 2014年 / 19卷 / 01期

基金：

欧洲研究理事会;

关键词：

ENDOTHELIAL-CELL METABOLISM; GROWTH-FACTOR; FRUCTOSE 2,6-BISPHOSPHATE; CANCER; DISEASE; 6-PHOSPHOFRUCTO-2-KINASE; RETINOPATHY; THERAPY; PREMATURITY; INHIBITION;

D O I：

10.1016/j.cmet.2013.11.008

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

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.

引用

页码：37 / 48

页数：12

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