title: Glycolytic regulation of cell rearrangement in angiogenesis.
abstract: During vessel sprouting, endothelial cells (ECs) dynamically rearrange positions in the sprout to compete for the tip position. We recently identified a key role for the glycolytic activator PFKFB3 in vessel sprouting by regulating cytoskeleton remodelling, migration and tip cell competitiveness. It is, however, unknown how glycolysis regulates EC rearrangement during vessel sprouting. Here we report that computational simulations, validated by experimentation, predict that glycolytic production of ATP drives EC rearrangement by promoting filopodia formation and reducing intercellular adhesion. Notably, the simulations correctly predicted that blocking PFKFB3 normalizes the disturbed EC rearrangement in high VEGF conditions, as occurs during pathological angiogenesis. This interdisciplinary study integrates EC metabolism in vessel sprouting, yielding mechanistic insight in the control of vessel sprouting by glycolysis, and suggesting anti-glycolytic therapy for vessel normalization in cancer and non-malignant diseases.
authors.affiliation: Department of Oncology, Laboratory of Angiogenesis and Vascular Metabolism, KU Leuven, Herestraat 49 box 912, B-3000 Leuven, Belgium.|Vesalius Research Center, Laboratory of Angiogenesis and Vascular Metabolism, VIB, Herestraat 49 box 912, B-3000 Leuven, Belgium.
authors.forename: Bert
authors.initials: B
authors.lastname: Cruys
authors.affiliation: Department of Oncology, Laboratory of Angiogenesis and Vascular Metabolism, KU Leuven, Herestraat 49 box 912, B-3000 Leuven, Belgium.|Vesalius Research Center, Laboratory of Angiogenesis and Vascular Metabolism, VIB, Herestraat 49 box 912, B-3000 Leuven, Belgium.
authors.forename: Brian W
authors.initials: BW
authors.lastname: Wong
authors.affiliation: Department of Oncology, Laboratory of Angiogenesis and Vascular Metabolism, KU Leuven, Herestraat 49 box 912, B-3000 Leuven, Belgium.|Vesalius Research Center, Laboratory of Angiogenesis and Vascular Metabolism, VIB, Herestraat 49 box 912, B-3000 Leuven, Belgium.
authors.forename: Anna
authors.initials: A
authors.lastname: Kuchnio
authors.affiliation: Department of Oncology, Laboratory of Angiogenesis and Vascular Metabolism, KU Leuven, Herestraat 49 box 912, B-3000 Leuven, Belgium.|Vesalius Research Center, Laboratory of Angiogenesis and Vascular Metabolism, VIB, Herestraat 49 box 912, B-3000 Leuven, Belgium.
authors.forename: Dries
authors.initials: D
authors.lastname: Verdegem
authors.affiliation: Department of Oncology, Laboratory of Angiogenesis and Vascular Metabolism, KU Leuven, Herestraat 49 box 912, B-3000 Leuven, Belgium.|Vesalius Research Center, Laboratory of Angiogenesis and Vascular Metabolism, VIB, Herestraat 49 box 912, B-3000 Leuven, Belgium.
authors.forename: Anna Rita
authors.initials: AR
authors.lastname: Cantelmo
authors.affiliation: Department of Oncology, Laboratory of Angiogenesis and Vascular Metabolism, KU Leuven, Herestraat 49 box 912, B-3000 Leuven, Belgium.|Vesalius Research Center, Laboratory of Angiogenesis and Vascular Metabolism, VIB, Herestraat 49 box 912, B-3000 Leuven, Belgium.
authors.forename: Lena-Christin
authors.initials: LC
authors.lastname: Conradi
authors.affiliation: Department of Oncology, Laboratory of Angiogenesis and Vascular Metabolism, KU Leuven, Herestraat 49 box 912, B-3000 Leuven, Belgium.|Vesalius Research Center, Laboratory of Angiogenesis and Vascular Metabolism, VIB, Herestraat 49 box 912, B-3000 Leuven, Belgium.
authors.forename: Saar
authors.initials: S
authors.lastname: Vandekeere
authors.affiliation: Department of Oncology, Laboratory of Angiogenesis and Vascular Metabolism, KU Leuven, Herestraat 49 box 912, B-3000 Leuven, Belgium.|Vesalius Research Center, Laboratory of Angiogenesis and Vascular Metabolism, VIB, Herestraat 49 box 912, B-3000 Leuven, Belgium.
authors.forename: Ann
authors.initials: A
authors.lastname: Bouché
authors.affiliation: Department of Oncology, Laboratory of Angiogenesis and Vascular Metabolism, KU Leuven, Herestraat 49 box 912, B-3000 Leuven, Belgium.|Vesalius Research Center, Laboratory of Angiogenesis and Vascular Metabolism, VIB, Herestraat 49 box 912, B-3000 Leuven, Belgium.
authors.forename: Ivo
authors.initials: I
authors.lastname: Cornelissen
authors.affiliation: Department of Oncology, Laboratory of Angiogenesis and Vascular Metabolism, KU Leuven, Herestraat 49 box 912, B-3000 Leuven, Belgium.|Vesalius Research Center, Laboratory of Angiogenesis and Vascular Metabolism, VIB, Herestraat 49 box 912, B-3000 Leuven, Belgium.
authors.forename: Stefan
authors.initials: S
authors.lastname: Vinckier
authors.affiliation: Life Sciences Group, Centrum Wiskunde and Informatica, Science Park 123, 1098 XG Amsterdam, The Netherlands.|Mathematical Institute, Leiden University, Niels Bohrweg 1, 2333 CA Leiden, The Netherlands.
authors.forename: Roeland M H
authors.initials: RM
authors.lastname: Merks
authors.affiliation: Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, 751 85 Uppsala, Sweden.|FIRC Institute of Molecular Oncology, Via Adamello 16, 20139 Milan, Italy.|Department of Oncology and Hemato-Oncology, Milan University, 20139 Milan, Italy.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Dejana
authors.affiliation: Department of Oncology, Vascular Patterning Laboratory, KU Leuven, Herestraat 49 box 912, B-3000 Leuven, Belgium.|Vesalius Research Center, Vascular Patterning Laboratory, VIB, Herestraat 49 box 912, B-3000 Leuven, Belgium.|Integrative Vascular Biology Laboratory, Max-Delbrück-Center for Molecular Medicine, Robert-Rössle-Strasse 10, D-13125 Berlin, Germany.
authors.forename: Holger
authors.initials: H
authors.lastname: Gerhardt
authors.affiliation: Department of Oncology, Laboratory of Angiogenesis and Vascular Metabolism, KU Leuven, Herestraat 49 box 912, B-3000 Leuven, Belgium.|Vesalius Research Center, Laboratory of Angiogenesis and Vascular Metabolism, VIB, Herestraat 49 box 912, B-3000 Leuven, Belgium.
authors.forename: Mieke
authors.initials: M
authors.lastname: Dewerchin
authors.affiliation: Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, 751 85 Uppsala, Sweden.|Department of Pathology, Computational Biology Laboratory, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, MA 02215, USA.
authors.forename: Katie
authors.initials: K
authors.lastname: Bentley
authors.affiliation: Department of Oncology, Laboratory of Angiogenesis and Vascular Metabolism, KU Leuven, Herestraat 49 box 912, B-3000 Leuven, Belgium.|Vesalius Research Center, Laboratory of Angiogenesis and Vascular Metabolism, VIB, Herestraat 49 box 912, B-3000 Leuven, Belgium.
authors.forename: Peter
authors.initials: P
authors.lastname: Carmeliet
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D015703:Antigens, CD / Q000378:metabolism; D015820:Cadherins / Q000037:antagonists & inhibitors / Q000378:metabolism; D003198:Computer Simulation; D055785:Gene Knockdown Techniques; D006019:Glycolysis / Q000187:drug effects; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D008954:Models, Biological; D018919:Neovascularization, Physiologic / Q000187:drug effects; D025481:Phosphofructokinase-2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D011554:Pseudopodia / Q000187:drug effects / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D000099152:Cadherin 5
chemical_list: D000255:Adenosine Triphosphate; D015703:Antigens, CD; D015820:Cadherins; D007211:Indoles; D025481:Phosphofructokinase-2; D011725:Pyridines; D011758:Pyrroles; D042461:Vascular Endothelial Growth Factor A; D000099152:Cadherin 5; C527590:3-(3-pyridinyl)-1-(4-pyridinyl)-2-propen-1-one; C116890:Semaxinib