title: Angiogenesis revisited - role and therapeutic potential of targeting endothelial metabolism.
abstract: Clinically approved therapies that target angiogenesis in tumors and ocular diseases focus on controlling pro-angiogenic growth factors in order to reduce aberrant microvascular growth. Although research on angiogenesis has revealed key mechanisms that regulate tissue vascularization, therapeutic success has been limited owing to insufficient efficacy, refractoriness and tumor resistance. Emerging concepts suggest that, in addition to growth factors, vascular metabolism also regulates angiogenesis and is a viable target for manipulating the microvasculature. Recent studies show that endothelial cells rely on glycolysis for ATP production, and that the key glycolytic regulator 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3) regulates angiogenesis by controlling the balance of tip versus stalk cells. As endothelial cells acquire a tip cell phenotype, they increase glycolytic production of ATP for sprouting. Furthermore, pharmacological blockade of PFKFB3 causes a transient, partial reduction in glycolysis, and reduces pathological angiogenesis with minimal systemic harm. Although further assessment of endothelial cell metabolism is necessary, these results represent a paradigm shift in anti-angiogenic therapy from targeting angiogenic factors to focusing on vascular metabolism, warranting research on the metabolic pathways that govern angiogenesis.
authors.affiliation: Laboratory of Angiogenesis and Neurovascular link, Vesalius Research Center, VIB, B-3000 Leuven, Belgium Laboratory of Angiogenesis and Neurovascular link, Department of Oncology, KU Leuven, B-3000 Leuven, Belgium.
authors.forename: Peter
authors.initials: P
authors.lastname: Stapor
authors.affiliation: Laboratory of Angiogenesis and Neurovascular link, Vesalius Research Center, VIB, B-3000 Leuven, Belgium Laboratory of Angiogenesis and Neurovascular link, Department of Oncology, KU Leuven, B-3000 Leuven, Belgium.
authors.forename: Xingwu
authors.initials: X
authors.lastname: Wang
authors.affiliation: Laboratory of Angiogenesis and Neurovascular link, Vesalius Research Center, VIB, B-3000 Leuven, Belgium Laboratory of Angiogenesis and Neurovascular link, Department of Oncology, KU Leuven, B-3000 Leuven, Belgium.
authors.forename: Jermaine
authors.initials: J
authors.lastname: Goveia
authors.affiliation: Laboratory of Angiogenesis and Neurovascular link, Vesalius Research Center, VIB, B-3000 Leuven, Belgium Laboratory of Angiogenesis and Neurovascular link, Department of Oncology, KU Leuven, B-3000 Leuven, Belgium.
authors.forename: Stijn
authors.initials: S
authors.lastname: Moens
authors.affiliation: Laboratory of Angiogenesis and Neurovascular link, Vesalius Research Center, VIB, B-3000 Leuven, Belgium Laboratory of Angiogenesis and Neurovascular link, Department of Oncology, KU Leuven, B-3000 Leuven, Belgium peter.carmeliet@vib-kuleuven.be.
authors.forename: Peter
authors.initials: P
authors.lastname: Carmeliet
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D020533:Angiogenesis Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism*; D006019:Glycolysis / Q000187:drug effects; D006801:Humans; D058990:Molecular Targeted Therapy; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000378:metabolism; D018919:Neovascularization, Physiologic; D025481:Phosphofructokinase-2 / Q000037:antagonists & inhibitors
chemical_list: D020533:Angiogenesis Inhibitors; D000255:Adenosine Triphosphate; C107345:PFKFB3 protein, human; D025481:Phosphofructokinase-2
keywords: Angiogenesis; Anti-angiogenesis therapy; Glycolysis; Metabolism