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      The role of glycolysis and mitochondrial respiration in the formation and functioning of endothelial tip cells during angiogenesis


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          During sprouting angiogenesis, an individual endothelial tip cell grows out from a pre-existing vascular network and guides following and proliferating stalk cells to form a new vessel. Metabolic pathways such as glycolysis and mitochondrial respiration as the major sources of adenosine 5′-triphosphate (ATP) for energy production are differentially activated in these types of endothelial cells (ECs) during angiogenesis. Therefore, we studied energy metabolism during angiogenesis in more detail in tip cell and non-tip cell human umbilical vein ECs. Small interfering RNA was used to inhibit transcription of glycolytic enzymes PFKFB3 or LDHA and mitochondrial enzyme PDHA1 to test whether inhibition of these specific pathways affects tip cell differentiation and sprouting angiogenesis in vitro and in vivo. We show that glycolysis is essential for tip cell differentiation, whereas both glycolysis and mitochondrial respiration occur during proliferation of non-tip cells and in sprouting angiogenesis in vitro and in vivo. Finally, we demonstrate that inhibition of mitochondrial respiration causes adaptation of EC metabolism by increasing glycolysis and vice versa. In conclusion, our studies show a complex but flexible role of the different metabolic pathways to produce ATP in the regulation of tip cell and non-tip cell differentiation and functioning during sprouting angiogenesis.

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          Most cited references56

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              Lactate Metabolism in Human Lung Tumors

              Cancer cells consume glucose and secrete lactate in culture. It is unknown whether lactate contributes to energy metabolism in living tumors. We previously reported that human non-small cell lung cancers (NSCLC) oxidize glucose in the tricarboxylic acid (TCA) cycle. Here we show that lactate is also a TCA cycle carbon source for NSCLC. In human NSCLC, evidence of lactate utilization was most apparent in tumors with high 18 fluorodeoxyglucose uptake and aggressive oncological behavior. Infusing human NSCLC patients with 13 C-lactate revealed extensive labeling of TCA cycle metabolites. In mice, deleting monocarboxylate transporter-1 (MCT1) from tumor cells eliminated lactate-dependent metabolite labeling, confirming tumor-cell autonomous lactate uptake. Strikingly, directly comparing lactate and glucose metabolism in vivo indicated that lactate's contribution to the TCA cycle predominates. The data indicate that tumors, including bona fide human NSCLC, can use lactate as a fuel in vivo. Human non-small cell lung cancer preferentially utilizes lactate over glucose to fuel TCA cycle and sustain tumor metabolism in vivo.

                Author and article information

                Sci Rep
                Sci Rep
                Scientific Reports
                Nature Publishing Group UK (London )
                30 August 2019
                30 August 2019
                : 9
                : 12608
                [1 ]ISNI 0000000084992262, GRID grid.7177.6, Ocular Angiogenesis Group, Department of Ophthalmology, , Amsterdam Cardiovascular Sciences and Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, ; Meibergdreef 9, Amsterdam, The Netherlands
                [2 ]ISNI 0000000084992262, GRID grid.7177.6, Department of Medical Biology, Amsterdam Cardiovascular Sciences and Cancer Center Amsterdam, Amsterdam UMC, , University of Amsterdam, ; Meibergdreef 9, Amsterdam, The Netherlands
                [3 ]Molecular Pharmacology Group, School of Pharmaceutical Sciences, Faculty of Sciences, University of Lausanne and University of Geneva, Geneva, Switzerland
                [4 ]ISNI 0000000084992262, GRID grid.7177.6, Laboratory Genetic Metabolic Diseases, Amsterdam Gastroenterology and Metabolism, Amsterdam Cardiovascular Sciences, Amsterdam UMC, , University of Amsterdam, ; Meibergdreef 9, Amsterdam, The Netherlands
                [5 ]ISNI 0000 0004 0637 0790, GRID grid.419523.8, Department of Genetic Toxicology and Cancer Biology, , National Institute of Biology, ; Ljubljana, Slovenia
                [6 ]ISNI 0000 0001 2165 4204, GRID grid.9851.5, Department of Ophthalmology, , University of Lausanne, Jules-Gonin Eye Hospital, Fondation Asile des Aveugles, ; Lausanne, Switzerland
                Author information
                © The Author(s) 2019

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                : 4 April 2019
                : 1 August 2019
                Funded by: UitZicht
                Funded by: UitZicht (Grant 2018-26, 2017-29 and 2015-19) Stichting tot Verbetering van het Lot der Blinden Rotterdamse Stichting Blindenbelangen (Grant B20140049) Stichting voor Ooglijders Stichting Blindenhulp Edmond en Marianne Blaauw Fonds voor Oogheelkunde
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                © The Author(s) 2019

                cell growth,mechanisms of disease,angiogenesis
                cell growth, mechanisms of disease, angiogenesis


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