XRole of PFKFB3-driven glycolysis in vessel sprouting

Katrien De Bock; Maria Georgiadou; Sandra Schoors; Anna Kuchnio; Brian W. Wong; Anna Rita Cantelmo; Annelies Quaegebeur; Bart Ghesquière; Sandra Cauwenberghs; Guy Eelen; Li Kun Phng; Inge Betz; Bieke Tembuyser; Katleen Brepoels; Jonathan Welti; Ilse Geudens; Inmaculada Segura; Bert Cruys; Franscesco Bifari; Ilaria Decimo; Raquel Blanco; Sabine Wyns; Jeroen Vangindertael; Susana Rocha; Russel T. Collins; Sebastian Munck; Dirk Daelemans; Hiromi Imamura; Roland Devlieger; Mark Rider; Paul P. Van Veldhoven; Frans Schuit; Ramon Bartrons; Johan Hofkens; Peter Fraisl; Sucheta Telang; Ralph J. Deberardinis; Luc Schoonjans; Stefan Vinckier; Jason Chesney; Holger Gerhardt; Mieke Dewerchin; Peter Carmeliet

doi:10.1016/j.cell.2013.06.037

XRole of PFKFB3-driven glycolysis in vessel sprouting

Katrien De Bock, Maria Georgiadou, Sandra Schoors, Anna Kuchnio, Brian W. Wong, Anna Rita Cantelmo, Annelies Quaegebeur, Bart Ghesquière, Sandra Cauwenberghs, Guy Eelen, Li Kun Phng, Inge Betz, Bieke Tembuyser, Katleen Brepoels, Jonathan Welti, Ilse Geudens, Inmaculada Segura, Bert Cruys, Franscesco Bifari, Ilaria DecimoRaquel Blanco, Sabine Wyns, Jeroen Vangindertael, Susana Rocha, Russel T. Collins, Sebastian Munck, Dirk Daelemans, Hiromi Imamura, Roland Devlieger, Mark Rider, Paul P. Van Veldhoven, Frans Schuit, Ramon Bartrons, Johan Hofkens, Peter Fraisl, Sucheta Telang, Ralph J. Deberardinis, Luc Schoonjans, Stefan Vinckier, Jason Chesney, Holger Gerhardt, Mieke Dewerchin, Peter Carmeliet

Research output: Contribution to journal › Article › peer-review

1017 Scopus citations

Abstract

Vessel sprouting by migrating tip and proliferating stalk endothelial cells (ECs) is controlled by genetic signals (such as Notch), but it is unknown whether metabolism also regulates this process. Here, we show that ECs relied on glycolysis rather than on oxidative phosphorylation for ATP production and that loss of the glycolytic activator PFKFB3 in ECs impaired vessel formation. Mechanistically, PFKFB3 not only regulated EC proliferation but also controlled the formation of filopodia/lamellipodia and directional migration, in part by compartmentalizing with F-actin in motile protrusions. Mosaic in vitro and in vivo sprouting assays further revealed that PFKFB3 overexpression overruled the pro-stalk activity of Notch, whereas PFKFB3 deficiency impaired tip cell formation upon Notch blockade, implying that glycolysis regulates vessel branching.

Original language	English (US)
Pages (from-to)	X651-663
Journal	Cell
Volume	154
Issue number	3
DOIs	https://doi.org/10.1016/j.cell.2013.06.037
State	Published - Aug 1 2013

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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10.1016/j.cell.2013.06.037

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De Bock, K., Georgiadou, M., Schoors, S., Kuchnio, A., Wong, B. W., Cantelmo, A. R., Quaegebeur, A., Ghesquière, B., Cauwenberghs, S., Eelen, G., Phng, L. K., Betz, I., Tembuyser, B., Brepoels, K., Welti, J., Geudens, I., Segura, I., Cruys, B., Bifari, F., ... Carmeliet, P. (2013). XRole of PFKFB3-driven glycolysis in vessel sprouting. Cell, 154(3), X651-663. https://doi.org/10.1016/j.cell.2013.06.037

De Bock, K, Georgiadou, M, Schoors, S, Kuchnio, A, Wong, BW, Cantelmo, AR, Quaegebeur, A, Ghesquière, B, Cauwenberghs, S, Eelen, G, Phng, LK, Betz, I, Tembuyser, B, Brepoels, K, Welti, J, Geudens, I, Segura, I, Cruys, B, Bifari, F, Decimo, I, Blanco, R, Wyns, S, Vangindertael, J, Rocha, S, Collins, RT, Munck, S, Daelemans, D, Imamura, H, Devlieger, R, Rider, M, Van Veldhoven, PP, Schuit, F, Bartrons, R, Hofkens, J, Fraisl, P, Telang, S, Deberardinis, RJ, Schoonjans, L, Vinckier, S, Chesney, J, Gerhardt, H, Dewerchin, M & Carmeliet, P 2013, 'XRole of PFKFB3-driven glycolysis in vessel sprouting', Cell, vol. 154, no. 3, pp. X651-663. https://doi.org/10.1016/j.cell.2013.06.037

@article{f474ea74306443a58c68951874886d23,

title = "XRole of PFKFB3-driven glycolysis in vessel sprouting",

abstract = "Vessel sprouting by migrating tip and proliferating stalk endothelial cells (ECs) is controlled by genetic signals (such as Notch), but it is unknown whether metabolism also regulates this process. Here, we show that ECs relied on glycolysis rather than on oxidative phosphorylation for ATP production and that loss of the glycolytic activator PFKFB3 in ECs impaired vessel formation. Mechanistically, PFKFB3 not only regulated EC proliferation but also controlled the formation of filopodia/lamellipodia and directional migration, in part by compartmentalizing with F-actin in motile protrusions. Mosaic in vitro and in vivo sprouting assays further revealed that PFKFB3 overexpression overruled the pro-stalk activity of Notch, whereas PFKFB3 deficiency impaired tip cell formation upon Notch blockade, implying that glycolysis regulates vessel branching.",

author = "{De Bock}, Katrien and Maria Georgiadou and Sandra Schoors and Anna Kuchnio and Wong, {Brian W.} and Cantelmo, {Anna Rita} and Annelies Quaegebeur and Bart Ghesqui{\`e}re and Sandra Cauwenberghs and Guy Eelen and Phng, {Li Kun} and Inge Betz and Bieke Tembuyser and Katleen Brepoels and Jonathan Welti and Ilse Geudens and Inmaculada Segura and Bert Cruys and Franscesco Bifari and Ilaria Decimo and Raquel Blanco and Sabine Wyns and Jeroen Vangindertael and Susana Rocha and Collins, {Russel T.} and Sebastian Munck and Dirk Daelemans and Hiromi Imamura and Roland Devlieger and Mark Rider and {Van Veldhoven}, {Paul P.} and Frans Schuit and Ramon Bartrons and Johan Hofkens and Peter Fraisl and Sucheta Telang and Deberardinis, {Ralph J.} and Luc Schoonjans and Stefan Vinckier and Jason Chesney and Holger Gerhardt and Mieke Dewerchin and Peter Carmeliet",

note = "Funding Information: We thank R. Adams for VE-cadherin(PAC)-Cre ERT2 mice and L. Notebaert for help with the figures. K.D.B., B.G., and I.S. are postdoctoral fellows of the FWO. M.G. and S.S. received funding as Emmanuel Vanderschueren fellows of the VLK. A.R.C. is funded by Fondazione Umberto Veronesi. B.W.W. received funding from the FWO and Marie Curie Foundation. A.K. and A.Q. are PhD FWO fellows. S.S. and B.C. are funded by the IWT. P.C. is supported by the Federal Government of Belgium (grant IUAP7/03), the Flemish Government (Methusalem funding), Concerted Research Activities Belgium (grant GOA2006/11), the FWO (grants G.0652.08, G.0692.09, G.0532.10, G.0817.11, and 1.5.202.10.N.00), the Foundation Leducq Transatlantic Network (ARTEMIS), and the ERC (advanced research grant EU-ERC269073). H.G. receives support from Cancer Research UK, the Lister Institute of Preventive Medicine, ARTEMIS, and the ERC (starting grant REshape 311719). L.K.P. and R.B. are supported by HFSP fellowships. P.C. is an inventor on patent applications claiming subject matter related to the results described in this paper. R.J.D. is a member of the scientific advisory board of Peleton Therapeutics. J.C. and S.T. are coinventors of U.S. patent 8,088,385 (PFKFB3 inhibitors for the treatment of proliferative cancer). ",

year = "2013",

month = aug,

day = "1",

doi = "10.1016/j.cell.2013.06.037",

language = "English (US)",

volume = "154",

pages = "X651--663",

journal = "Cell",

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publisher = "Cell Press",

number = "3",

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TY - JOUR

T1 - XRole of PFKFB3-driven glycolysis in vessel sprouting

AU - De Bock, Katrien

AU - Georgiadou, Maria

AU - Schoors, Sandra

AU - Kuchnio, Anna

AU - Wong, Brian W.

AU - Cantelmo, Anna Rita

AU - Quaegebeur, Annelies

AU - Ghesquière, Bart

AU - Cauwenberghs, Sandra

AU - Eelen, Guy

AU - Phng, Li Kun

AU - Betz, Inge

AU - Tembuyser, Bieke

AU - Brepoels, Katleen

AU - Welti, Jonathan

AU - Geudens, Ilse

AU - Segura, Inmaculada

AU - Cruys, Bert

AU - Bifari, Franscesco

AU - Decimo, Ilaria

AU - Blanco, Raquel

AU - Wyns, Sabine

AU - Vangindertael, Jeroen

AU - Rocha, Susana

AU - Collins, Russel T.

AU - Munck, Sebastian

AU - Daelemans, Dirk

AU - Imamura, Hiromi

AU - Devlieger, Roland

AU - Rider, Mark

AU - Van Veldhoven, Paul P.

AU - Schuit, Frans

AU - Bartrons, Ramon

AU - Hofkens, Johan

AU - Fraisl, Peter

AU - Telang, Sucheta

AU - Deberardinis, Ralph J.

AU - Schoonjans, Luc

AU - Vinckier, Stefan

AU - Chesney, Jason

AU - Gerhardt, Holger

AU - Dewerchin, Mieke

AU - Carmeliet, Peter

N1 - Funding Information: We thank R. Adams for VE-cadherin(PAC)-Cre ERT2 mice and L. Notebaert for help with the figures. K.D.B., B.G., and I.S. are postdoctoral fellows of the FWO. M.G. and S.S. received funding as Emmanuel Vanderschueren fellows of the VLK. A.R.C. is funded by Fondazione Umberto Veronesi. B.W.W. received funding from the FWO and Marie Curie Foundation. A.K. and A.Q. are PhD FWO fellows. S.S. and B.C. are funded by the IWT. P.C. is supported by the Federal Government of Belgium (grant IUAP7/03), the Flemish Government (Methusalem funding), Concerted Research Activities Belgium (grant GOA2006/11), the FWO (grants G.0652.08, G.0692.09, G.0532.10, G.0817.11, and 1.5.202.10.N.00), the Foundation Leducq Transatlantic Network (ARTEMIS), and the ERC (advanced research grant EU-ERC269073). H.G. receives support from Cancer Research UK, the Lister Institute of Preventive Medicine, ARTEMIS, and the ERC (starting grant REshape 311719). L.K.P. and R.B. are supported by HFSP fellowships. P.C. is an inventor on patent applications claiming subject matter related to the results described in this paper. R.J.D. is a member of the scientific advisory board of Peleton Therapeutics. J.C. and S.T. are coinventors of U.S. patent 8,088,385 (PFKFB3 inhibitors for the treatment of proliferative cancer).

PY - 2013/8/1

Y1 - 2013/8/1

N2 - Vessel sprouting by migrating tip and proliferating stalk endothelial cells (ECs) is controlled by genetic signals (such as Notch), but it is unknown whether metabolism also regulates this process. Here, we show that ECs relied on glycolysis rather than on oxidative phosphorylation for ATP production and that loss of the glycolytic activator PFKFB3 in ECs impaired vessel formation. Mechanistically, PFKFB3 not only regulated EC proliferation but also controlled the formation of filopodia/lamellipodia and directional migration, in part by compartmentalizing with F-actin in motile protrusions. Mosaic in vitro and in vivo sprouting assays further revealed that PFKFB3 overexpression overruled the pro-stalk activity of Notch, whereas PFKFB3 deficiency impaired tip cell formation upon Notch blockade, implying that glycolysis regulates vessel branching.

AB - Vessel sprouting by migrating tip and proliferating stalk endothelial cells (ECs) is controlled by genetic signals (such as Notch), but it is unknown whether metabolism also regulates this process. Here, we show that ECs relied on glycolysis rather than on oxidative phosphorylation for ATP production and that loss of the glycolytic activator PFKFB3 in ECs impaired vessel formation. Mechanistically, PFKFB3 not only regulated EC proliferation but also controlled the formation of filopodia/lamellipodia and directional migration, in part by compartmentalizing with F-actin in motile protrusions. Mosaic in vitro and in vivo sprouting assays further revealed that PFKFB3 overexpression overruled the pro-stalk activity of Notch, whereas PFKFB3 deficiency impaired tip cell formation upon Notch blockade, implying that glycolysis regulates vessel branching.

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VL - 154

SP - X651-663

JO - Cell

JF - Cell

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ER -

XRole of PFKFB3-driven glycolysis in vessel sprouting

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