Journal
JOURNAL OF CELL SCIENCE
Volume 127, Issue 20, Pages 4331-4341Publisher
COMPANY OF BIOLOGISTS LTD
DOI: 10.1242/jcs.153908
Keywords
Angiogenesis; Anti-angiogenesis therapy; Glycolysis; Metabolism
Categories
Funding
- Belgian American Educational Foundation (BAEF)
- FWO Postdoctoral Fellowship
- Bijzonder onderzoeksfond fellowship (BOF)
- Emmanuel Vanderschueren fellowship from the Flemish Association against Cancer (VLK)
- Federal Government Belgium grant
- Flemish Government
- Belgian Science Fund (FWO) from the University of Leuven
- Foundation of Leducq Transatlantic Artemic Network, a European Research Council (ERC) Advanced Research Grant
- AXA Research Fund
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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.
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