Fatty acid carbon is essential for dNTP synthesis in endothelial cells
The metabolism of endothelial cells during vessel sprouting remains poorly studied. Here we report that endothelial loss of CPT1A, a rate-limiting enzyme of fatty acid oxidation (FAO), causes vascular sprouting defects due to impaired proliferation, not migration, of human and murine endothelial cel...
Ausführliche Beschreibung
Gespeichert in:
| Autor*in: |
Sandra Schoors [verfasserIn] |
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| Format: |
Artikel |
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| Sprache: |
Englisch |
| Erschienen: |
2015 |
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| Übergeordnetes Werk: |
Enthalten in: Nature - London : Macmillan Publishers Limited, part of Springer Nature, 1869, 520(2015), 7546, Seite 192-197 |
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| Übergeordnetes Werk: |
volume:520 ; year:2015 ; number:7546 ; pages:192-197 |
| Links: |
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| DOI / URN: |
10.1038/nature14362 |
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| Katalog-ID: |
OLC1962479145 |
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| 245 | 1 | 0 | |a Fatty acid carbon is essential for dNTP synthesis in endothelial cells |
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| 520 | |a The metabolism of endothelial cells during vessel sprouting remains poorly studied. Here we report that endothelial loss of CPT1A, a rate-limiting enzyme of fatty acid oxidation (FAO), causes vascular sprouting defects due to impaired proliferation, not migration, of human and murine endothelial cells. Reduction of FAO in endothelial cells did not cause energy depletion or disturb redox homeostasis, but impaired de novo nucleotide synthesis for DNA replication. Isotope labelling studies in control endothelial cells showed that fatty acid carbons substantially replenished the Krebs cycle, and were incorporated into aspartate (a nucleotide precursor), uridine monophosphate (a precursor of pyrimidine nucleoside triphosphates) and DNA. CPT1A silencing reduced these processes and depleted endothelial cell stores of aspartate and deoxyribonucleoside triphosphates. Acetate (metabolized to acetyl-CoA, thereby substituting for the depleted FAO-derived acetyl-CoA) or a nucleoside mix rescued the phenotype of CPT1A-silenced endothelial cells. Finally, CPT1 blockade inhibited pathological ocular angiogenesis in mice, suggesting a novel strategy for blocking angiogenesis. | ||
| 650 | 4 | |a Kinases | |
| 650 | 4 | |a Protein synthesis | |
| 650 | 4 | |a Carbon | |
| 650 | 4 | |a Cells | |
| 650 | 4 | |a Fatty acids | |
| 650 | 4 | |a Angiogenesis | |
| 650 | 4 | |a Deoxyribonucleic acid--DNA | |
| 650 | 4 | |a Glucose | |
| 650 | 4 | |a Proteins | |
| 650 | 4 | |a Retinopathy of Prematurity - pathology | |
| 650 | 4 | |a Endothelial Cells - drug effects | |
| 650 | 4 | |a Carbon - metabolism | |
| 650 | 4 | |a Acetic Acid - pharmacology | |
| 650 | 4 | |a Human Umbilical Vein Endothelial Cells - drug effects | |
| 650 | 4 | |a Blood Vessels - drug effects | |
| 650 | 4 | |a Retinopathy of Prematurity - drug therapy | |
| 650 | 4 | |a Blood Vessels - cytology | |
| 650 | 4 | |a Nucleotides - biosynthesis | |
| 650 | 4 | |a Human Umbilical Vein Endothelial Cells - pathology | |
| 650 | 4 | |a Cell Proliferation - drug effects | |
| 650 | 4 | |a Carnitine O-Palmitoyltransferase - antagonists & inhibitors | |
| 650 | 4 | |a Carnitine O-Palmitoyltransferase - metabolism | |
| 650 | 4 | |a Fatty Acids - chemistry | |
| 650 | 4 | |a Neovascularization, Pathologic - metabolism | |
| 650 | 4 | |a Human Umbilical Vein Endothelial Cells - metabolism | |
| 650 | 4 | |a Adenosine Triphosphate - metabolism | |
| 650 | 4 | |a Neovascularization, Pathologic - drug therapy | |
| 650 | 4 | |a Glucose - metabolism | |
| 650 | 4 | |a Retinopathy of Prematurity - metabolism | |
| 650 | 4 | |a Nucleotides - chemistry | |
| 650 | 4 | |a Endothelial Cells - cytology | |
| 650 | 4 | |a Nucleotides - pharmacology | |
| 650 | 4 | |a Fatty Acids - metabolism | |
| 650 | 4 | |a Carnitine O-Palmitoyltransferase - deficiency | |
| 650 | 4 | |a Carnitine O-Palmitoyltransferase - genetics | |
| 650 | 4 | |a Endothelial Cells - metabolism | |
| 650 | 4 | |a Human Umbilical Vein Endothelial Cells - cytology | |
| 650 | 4 | |a Neovascularization, Pathologic - pathology | |
| 650 | 4 | |a DNA - biosynthesis | |
| 650 | 4 | |a Blood Vessels - pathology | |
| 650 | 4 | |a Blood Vessels - metabolism | |
| 650 | 4 | |a Oxidation-Reduction - drug effects | |
| 650 | 4 | |a Endothelial Cells - enzymology | |
| 650 | 4 | |a Deoxyribonucleotides | |
| 650 | 4 | |a Physiological aspects | |
| 650 | 4 | |a Endothelium | |
| 700 | 0 | |a Ulrike Bruning |4 oth | |
| 700 | 0 | |a Rindert Missiaen |4 oth | |
| 700 | 0 | |a Karla C S Queiroz |4 oth | |
| 700 | 0 | |a Gitte Borgers |4 oth | |
| 700 | 0 | |a Ilaria Elia |4 oth | |
| 700 | 0 | |a Annalisa Zecchin |4 oth | |
| 700 | 0 | |a Anna Rita Cantelmo |4 oth | |
| 700 | 0 | |a Stefan Christen |4 oth | |
| 700 | 0 | |a Jermaine Goveia |4 oth | |
| 700 | 0 | |a Ward Heggermont |4 oth | |
| 700 | 0 | |a Lucica Goddë |4 oth | |
| 700 | 0 | |a Stefan Vinckier |4 oth | |
| 700 | 0 | |a Paul P VanVeldhoven |4 oth | |
| 700 | 0 | |a Guy Eelen |4 oth | |
| 700 | 0 | |a Luc Schoonjans |4 oth | |
| 700 | 0 | |a Holger Gerhardt |4 oth | |
| 700 | 0 | |a Mieke Dewerchin |4 oth | |
| 700 | 0 | |a Myriam Baes |4 oth | |
| 700 | 0 | |a Katrien De Bock |4 oth | |
| 700 | 0 | |a Bart Ghesquière |4 oth | |
| 700 | 0 | |a Sophia Y Lunt |4 oth | |
| 700 | 0 | |a Sarah-Maria Fendt |4 oth | |
| 700 | 0 | |a Peter Carmeliet |4 oth | |
| 773 | 0 | 8 | |i Enthalten in |t Nature |d London : Macmillan Publishers Limited, part of Springer Nature, 1869 |g 520(2015), 7546, Seite 192-197 |w (DE-627)129292834 |w (DE-600)120714-3 |w (DE-576)014473941 |x 0028-0836 |7 nnns |
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| 856 | 4 | 2 | |u http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=4413024&tool=pmcentrez&rendertype=abstract |
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10.1038/nature14362 doi PQ20160617 (DE-627)OLC1962479145 (DE-599)GBVOLC1962479145 (PRQ)c3491-613c8b29dccc6cba09e995b642948eeba97aad6fa3c43a40626da0200ba90df00 (KEY)0072945020150000520754600192fattyacidcarbonisessentialfordntpsynthesisinendoth DE-627 ger DE-627 rakwb eng 070 500 DNB 500 AVZ BIODIV fid Sandra Schoors verfasserin aut Fatty acid carbon is essential for dNTP synthesis in endothelial cells 2015 Text txt rdacontent ohne Hilfsmittel zu benutzen n rdamedia Band nc rdacarrier The metabolism of endothelial cells during vessel sprouting remains poorly studied. Here we report that endothelial loss of CPT1A, a rate-limiting enzyme of fatty acid oxidation (FAO), causes vascular sprouting defects due to impaired proliferation, not migration, of human and murine endothelial cells. Reduction of FAO in endothelial cells did not cause energy depletion or disturb redox homeostasis, but impaired de novo nucleotide synthesis for DNA replication. Isotope labelling studies in control endothelial cells showed that fatty acid carbons substantially replenished the Krebs cycle, and were incorporated into aspartate (a nucleotide precursor), uridine monophosphate (a precursor of pyrimidine nucleoside triphosphates) and DNA. CPT1A silencing reduced these processes and depleted endothelial cell stores of aspartate and deoxyribonucleoside triphosphates. Acetate (metabolized to acetyl-CoA, thereby substituting for the depleted FAO-derived acetyl-CoA) or a nucleoside mix rescued the phenotype of CPT1A-silenced endothelial cells. Finally, CPT1 blockade inhibited pathological ocular angiogenesis in mice, suggesting a novel strategy for blocking angiogenesis. Kinases Protein synthesis Carbon Cells Fatty acids Angiogenesis Deoxyribonucleic acid--DNA Glucose Proteins Retinopathy of Prematurity - pathology Endothelial Cells - drug effects Carbon - metabolism Acetic Acid - pharmacology Human Umbilical Vein Endothelial Cells - drug effects Blood Vessels - drug effects Retinopathy of Prematurity - drug therapy Blood Vessels - cytology Nucleotides - biosynthesis Human Umbilical Vein Endothelial Cells - pathology Cell Proliferation - drug effects Carnitine O-Palmitoyltransferase - antagonists & inhibitors Carnitine O-Palmitoyltransferase - metabolism Fatty Acids - chemistry Neovascularization, Pathologic - metabolism Human Umbilical Vein Endothelial Cells - metabolism Adenosine Triphosphate - metabolism Neovascularization, Pathologic - drug therapy Glucose - metabolism Retinopathy of Prematurity - metabolism Nucleotides - chemistry Endothelial Cells - cytology Nucleotides - pharmacology Fatty Acids - metabolism Carnitine O-Palmitoyltransferase - deficiency Carnitine O-Palmitoyltransferase - genetics Endothelial Cells - metabolism Human Umbilical Vein Endothelial Cells - cytology Neovascularization, Pathologic - pathology DNA - biosynthesis Blood Vessels - pathology Blood Vessels - metabolism Oxidation-Reduction - drug effects Endothelial Cells - enzymology Deoxyribonucleotides Physiological aspects Endothelium Ulrike Bruning oth Rindert Missiaen oth Karla C S Queiroz oth Gitte Borgers oth Ilaria Elia oth Annalisa Zecchin oth Anna Rita Cantelmo oth Stefan Christen oth Jermaine Goveia oth Ward Heggermont oth Lucica Goddë oth Stefan Vinckier oth Paul P VanVeldhoven oth Guy Eelen oth Luc Schoonjans oth Holger Gerhardt oth Mieke Dewerchin oth Myriam Baes oth Katrien De Bock oth Bart Ghesquière oth Sophia Y Lunt oth Sarah-Maria Fendt oth Peter Carmeliet oth Enthalten in Nature London : Macmillan Publishers Limited, part of Springer Nature, 1869 520(2015), 7546, Seite 192-197 (DE-627)129292834 (DE-600)120714-3 (DE-576)014473941 0028-0836 nnns volume:520 year:2015 number:7546 pages:192-197 http://dx.doi.org/10.1038/nature14362 Volltext http://www.ncbi.nlm.nih.gov/pubmed/25830893 http://search.proquest.com/docview/1672890377 http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=4413024&tool=pmcentrez&rendertype=abstract GBV_USEFLAG_A SYSFLAG_A GBV_OLC FID-BIODIV SSG-OLC-PHY SSG-OLC-CHE SSG-OLC-MAT SSG-OLC-FOR SSG-OLC-SPO SSG-OLC-PHA SSG-OLC-DE-84 SSG-OPC-FOR GBV_ILN_11 GBV_ILN_21 GBV_ILN_22 GBV_ILN_30 GBV_ILN_40 GBV_ILN_47 GBV_ILN_55 GBV_ILN_59 GBV_ILN_60 GBV_ILN_62 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_100 GBV_ILN_101 GBV_ILN_110 GBV_ILN_120 GBV_ILN_154 GBV_ILN_160 GBV_ILN_168 GBV_ILN_170 GBV_ILN_171 GBV_ILN_211 GBV_ILN_267 GBV_ILN_290 GBV_ILN_294 GBV_ILN_601 GBV_ILN_647 GBV_ILN_754 GBV_ILN_2001 GBV_ILN_2002 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2015 GBV_ILN_2016 GBV_ILN_2018 GBV_ILN_2020 GBV_ILN_2026 GBV_ILN_2095 GBV_ILN_2116 GBV_ILN_2120 GBV_ILN_2121 GBV_ILN_2173 GBV_ILN_2219 GBV_ILN_2221 GBV_ILN_2279 GBV_ILN_2286 GBV_ILN_4012 GBV_ILN_4035 GBV_ILN_4046 GBV_ILN_4125 GBV_ILN_4219 GBV_ILN_4251 GBV_ILN_4277 GBV_ILN_4302 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4313 GBV_ILN_4314 GBV_ILN_4317 GBV_ILN_4320 GBV_ILN_4324 GBV_ILN_4700 AR 520 2015 7546 192-197 |
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10.1038/nature14362 doi PQ20160617 (DE-627)OLC1962479145 (DE-599)GBVOLC1962479145 (PRQ)c3491-613c8b29dccc6cba09e995b642948eeba97aad6fa3c43a40626da0200ba90df00 (KEY)0072945020150000520754600192fattyacidcarbonisessentialfordntpsynthesisinendoth DE-627 ger DE-627 rakwb eng 070 500 DNB 500 AVZ BIODIV fid Sandra Schoors verfasserin aut Fatty acid carbon is essential for dNTP synthesis in endothelial cells 2015 Text txt rdacontent ohne Hilfsmittel zu benutzen n rdamedia Band nc rdacarrier The metabolism of endothelial cells during vessel sprouting remains poorly studied. Here we report that endothelial loss of CPT1A, a rate-limiting enzyme of fatty acid oxidation (FAO), causes vascular sprouting defects due to impaired proliferation, not migration, of human and murine endothelial cells. Reduction of FAO in endothelial cells did not cause energy depletion or disturb redox homeostasis, but impaired de novo nucleotide synthesis for DNA replication. Isotope labelling studies in control endothelial cells showed that fatty acid carbons substantially replenished the Krebs cycle, and were incorporated into aspartate (a nucleotide precursor), uridine monophosphate (a precursor of pyrimidine nucleoside triphosphates) and DNA. CPT1A silencing reduced these processes and depleted endothelial cell stores of aspartate and deoxyribonucleoside triphosphates. Acetate (metabolized to acetyl-CoA, thereby substituting for the depleted FAO-derived acetyl-CoA) or a nucleoside mix rescued the phenotype of CPT1A-silenced endothelial cells. Finally, CPT1 blockade inhibited pathological ocular angiogenesis in mice, suggesting a novel strategy for blocking angiogenesis. Kinases Protein synthesis Carbon Cells Fatty acids Angiogenesis Deoxyribonucleic acid--DNA Glucose Proteins Retinopathy of Prematurity - pathology Endothelial Cells - drug effects Carbon - metabolism Acetic Acid - pharmacology Human Umbilical Vein Endothelial Cells - drug effects Blood Vessels - drug effects Retinopathy of Prematurity - drug therapy Blood Vessels - cytology Nucleotides - biosynthesis Human Umbilical Vein Endothelial Cells - pathology Cell Proliferation - drug effects Carnitine O-Palmitoyltransferase - antagonists & inhibitors Carnitine O-Palmitoyltransferase - metabolism Fatty Acids - chemistry Neovascularization, Pathologic - metabolism Human Umbilical Vein Endothelial Cells - metabolism Adenosine Triphosphate - metabolism Neovascularization, Pathologic - drug therapy Glucose - metabolism Retinopathy of Prematurity - metabolism Nucleotides - chemistry Endothelial Cells - cytology Nucleotides - pharmacology Fatty Acids - metabolism Carnitine O-Palmitoyltransferase - deficiency Carnitine O-Palmitoyltransferase - genetics Endothelial Cells - metabolism Human Umbilical Vein Endothelial Cells - cytology Neovascularization, Pathologic - pathology DNA - biosynthesis Blood Vessels - pathology Blood Vessels - metabolism Oxidation-Reduction - drug effects Endothelial Cells - enzymology Deoxyribonucleotides Physiological aspects Endothelium Ulrike Bruning oth Rindert Missiaen oth Karla C S Queiroz oth Gitte Borgers oth Ilaria Elia oth Annalisa Zecchin oth Anna Rita Cantelmo oth Stefan Christen oth Jermaine Goveia oth Ward Heggermont oth Lucica Goddë oth Stefan Vinckier oth Paul P VanVeldhoven oth Guy Eelen oth Luc Schoonjans oth Holger Gerhardt oth Mieke Dewerchin oth Myriam Baes oth Katrien De Bock oth Bart Ghesquière oth Sophia Y Lunt oth Sarah-Maria Fendt oth Peter Carmeliet oth Enthalten in Nature London : Macmillan Publishers Limited, part of Springer Nature, 1869 520(2015), 7546, Seite 192-197 (DE-627)129292834 (DE-600)120714-3 (DE-576)014473941 0028-0836 nnns volume:520 year:2015 number:7546 pages:192-197 http://dx.doi.org/10.1038/nature14362 Volltext http://www.ncbi.nlm.nih.gov/pubmed/25830893 http://search.proquest.com/docview/1672890377 http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=4413024&tool=pmcentrez&rendertype=abstract GBV_USEFLAG_A SYSFLAG_A GBV_OLC FID-BIODIV SSG-OLC-PHY SSG-OLC-CHE SSG-OLC-MAT SSG-OLC-FOR SSG-OLC-SPO SSG-OLC-PHA SSG-OLC-DE-84 SSG-OPC-FOR GBV_ILN_11 GBV_ILN_21 GBV_ILN_22 GBV_ILN_30 GBV_ILN_40 GBV_ILN_47 GBV_ILN_55 GBV_ILN_59 GBV_ILN_60 GBV_ILN_62 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_100 GBV_ILN_101 GBV_ILN_110 GBV_ILN_120 GBV_ILN_154 GBV_ILN_160 GBV_ILN_168 GBV_ILN_170 GBV_ILN_171 GBV_ILN_211 GBV_ILN_267 GBV_ILN_290 GBV_ILN_294 GBV_ILN_601 GBV_ILN_647 GBV_ILN_754 GBV_ILN_2001 GBV_ILN_2002 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2015 GBV_ILN_2016 GBV_ILN_2018 GBV_ILN_2020 GBV_ILN_2026 GBV_ILN_2095 GBV_ILN_2116 GBV_ILN_2120 GBV_ILN_2121 GBV_ILN_2173 GBV_ILN_2219 GBV_ILN_2221 GBV_ILN_2279 GBV_ILN_2286 GBV_ILN_4012 GBV_ILN_4035 GBV_ILN_4046 GBV_ILN_4125 GBV_ILN_4219 GBV_ILN_4251 GBV_ILN_4277 GBV_ILN_4302 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4313 GBV_ILN_4314 GBV_ILN_4317 GBV_ILN_4320 GBV_ILN_4324 GBV_ILN_4700 AR 520 2015 7546 192-197 |
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10.1038/nature14362 doi PQ20160617 (DE-627)OLC1962479145 (DE-599)GBVOLC1962479145 (PRQ)c3491-613c8b29dccc6cba09e995b642948eeba97aad6fa3c43a40626da0200ba90df00 (KEY)0072945020150000520754600192fattyacidcarbonisessentialfordntpsynthesisinendoth DE-627 ger DE-627 rakwb eng 070 500 DNB 500 AVZ BIODIV fid Sandra Schoors verfasserin aut Fatty acid carbon is essential for dNTP synthesis in endothelial cells 2015 Text txt rdacontent ohne Hilfsmittel zu benutzen n rdamedia Band nc rdacarrier The metabolism of endothelial cells during vessel sprouting remains poorly studied. Here we report that endothelial loss of CPT1A, a rate-limiting enzyme of fatty acid oxidation (FAO), causes vascular sprouting defects due to impaired proliferation, not migration, of human and murine endothelial cells. Reduction of FAO in endothelial cells did not cause energy depletion or disturb redox homeostasis, but impaired de novo nucleotide synthesis for DNA replication. Isotope labelling studies in control endothelial cells showed that fatty acid carbons substantially replenished the Krebs cycle, and were incorporated into aspartate (a nucleotide precursor), uridine monophosphate (a precursor of pyrimidine nucleoside triphosphates) and DNA. CPT1A silencing reduced these processes and depleted endothelial cell stores of aspartate and deoxyribonucleoside triphosphates. Acetate (metabolized to acetyl-CoA, thereby substituting for the depleted FAO-derived acetyl-CoA) or a nucleoside mix rescued the phenotype of CPT1A-silenced endothelial cells. Finally, CPT1 blockade inhibited pathological ocular angiogenesis in mice, suggesting a novel strategy for blocking angiogenesis. Kinases Protein synthesis Carbon Cells Fatty acids Angiogenesis Deoxyribonucleic acid--DNA Glucose Proteins Retinopathy of Prematurity - pathology Endothelial Cells - drug effects Carbon - metabolism Acetic Acid - pharmacology Human Umbilical Vein Endothelial Cells - drug effects Blood Vessels - drug effects Retinopathy of Prematurity - drug therapy Blood Vessels - cytology Nucleotides - biosynthesis Human Umbilical Vein Endothelial Cells - pathology Cell Proliferation - drug effects Carnitine O-Palmitoyltransferase - antagonists & inhibitors Carnitine O-Palmitoyltransferase - metabolism Fatty Acids - chemistry Neovascularization, Pathologic - metabolism Human Umbilical Vein Endothelial Cells - metabolism Adenosine Triphosphate - metabolism Neovascularization, Pathologic - drug therapy Glucose - metabolism Retinopathy of Prematurity - metabolism Nucleotides - chemistry Endothelial Cells - cytology Nucleotides - pharmacology Fatty Acids - metabolism Carnitine O-Palmitoyltransferase - deficiency Carnitine O-Palmitoyltransferase - genetics Endothelial Cells - metabolism Human Umbilical Vein Endothelial Cells - cytology Neovascularization, Pathologic - pathology DNA - biosynthesis Blood Vessels - pathology Blood Vessels - metabolism Oxidation-Reduction - drug effects Endothelial Cells - enzymology Deoxyribonucleotides Physiological aspects Endothelium Ulrike Bruning oth Rindert Missiaen oth Karla C S Queiroz oth Gitte Borgers oth Ilaria Elia oth Annalisa Zecchin oth Anna Rita Cantelmo oth Stefan Christen oth Jermaine Goveia oth Ward Heggermont oth Lucica Goddë oth Stefan Vinckier oth Paul P VanVeldhoven oth Guy Eelen oth Luc Schoonjans oth Holger Gerhardt oth Mieke Dewerchin oth Myriam Baes oth Katrien De Bock oth Bart Ghesquière oth Sophia Y Lunt oth Sarah-Maria Fendt oth Peter Carmeliet oth Enthalten in Nature London : Macmillan Publishers Limited, part of Springer Nature, 1869 520(2015), 7546, Seite 192-197 (DE-627)129292834 (DE-600)120714-3 (DE-576)014473941 0028-0836 nnns volume:520 year:2015 number:7546 pages:192-197 http://dx.doi.org/10.1038/nature14362 Volltext http://www.ncbi.nlm.nih.gov/pubmed/25830893 http://search.proquest.com/docview/1672890377 http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=4413024&tool=pmcentrez&rendertype=abstract GBV_USEFLAG_A SYSFLAG_A GBV_OLC FID-BIODIV SSG-OLC-PHY SSG-OLC-CHE SSG-OLC-MAT SSG-OLC-FOR SSG-OLC-SPO SSG-OLC-PHA SSG-OLC-DE-84 SSG-OPC-FOR GBV_ILN_11 GBV_ILN_21 GBV_ILN_22 GBV_ILN_30 GBV_ILN_40 GBV_ILN_47 GBV_ILN_55 GBV_ILN_59 GBV_ILN_60 GBV_ILN_62 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_100 GBV_ILN_101 GBV_ILN_110 GBV_ILN_120 GBV_ILN_154 GBV_ILN_160 GBV_ILN_168 GBV_ILN_170 GBV_ILN_171 GBV_ILN_211 GBV_ILN_267 GBV_ILN_290 GBV_ILN_294 GBV_ILN_601 GBV_ILN_647 GBV_ILN_754 GBV_ILN_2001 GBV_ILN_2002 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2015 GBV_ILN_2016 GBV_ILN_2018 GBV_ILN_2020 GBV_ILN_2026 GBV_ILN_2095 GBV_ILN_2116 GBV_ILN_2120 GBV_ILN_2121 GBV_ILN_2173 GBV_ILN_2219 GBV_ILN_2221 GBV_ILN_2279 GBV_ILN_2286 GBV_ILN_4012 GBV_ILN_4035 GBV_ILN_4046 GBV_ILN_4125 GBV_ILN_4219 GBV_ILN_4251 GBV_ILN_4277 GBV_ILN_4302 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4313 GBV_ILN_4314 GBV_ILN_4317 GBV_ILN_4320 GBV_ILN_4324 GBV_ILN_4700 AR 520 2015 7546 192-197 |
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10.1038/nature14362 doi PQ20160617 (DE-627)OLC1962479145 (DE-599)GBVOLC1962479145 (PRQ)c3491-613c8b29dccc6cba09e995b642948eeba97aad6fa3c43a40626da0200ba90df00 (KEY)0072945020150000520754600192fattyacidcarbonisessentialfordntpsynthesisinendoth DE-627 ger DE-627 rakwb eng 070 500 DNB 500 AVZ BIODIV fid Sandra Schoors verfasserin aut Fatty acid carbon is essential for dNTP synthesis in endothelial cells 2015 Text txt rdacontent ohne Hilfsmittel zu benutzen n rdamedia Band nc rdacarrier The metabolism of endothelial cells during vessel sprouting remains poorly studied. Here we report that endothelial loss of CPT1A, a rate-limiting enzyme of fatty acid oxidation (FAO), causes vascular sprouting defects due to impaired proliferation, not migration, of human and murine endothelial cells. Reduction of FAO in endothelial cells did not cause energy depletion or disturb redox homeostasis, but impaired de novo nucleotide synthesis for DNA replication. Isotope labelling studies in control endothelial cells showed that fatty acid carbons substantially replenished the Krebs cycle, and were incorporated into aspartate (a nucleotide precursor), uridine monophosphate (a precursor of pyrimidine nucleoside triphosphates) and DNA. CPT1A silencing reduced these processes and depleted endothelial cell stores of aspartate and deoxyribonucleoside triphosphates. Acetate (metabolized to acetyl-CoA, thereby substituting for the depleted FAO-derived acetyl-CoA) or a nucleoside mix rescued the phenotype of CPT1A-silenced endothelial cells. Finally, CPT1 blockade inhibited pathological ocular angiogenesis in mice, suggesting a novel strategy for blocking angiogenesis. Kinases Protein synthesis Carbon Cells Fatty acids Angiogenesis Deoxyribonucleic acid--DNA Glucose Proteins Retinopathy of Prematurity - pathology Endothelial Cells - drug effects Carbon - metabolism Acetic Acid - pharmacology Human Umbilical Vein Endothelial Cells - drug effects Blood Vessels - drug effects Retinopathy of Prematurity - drug therapy Blood Vessels - cytology Nucleotides - biosynthesis Human Umbilical Vein Endothelial Cells - pathology Cell Proliferation - drug effects Carnitine O-Palmitoyltransferase - antagonists & inhibitors Carnitine O-Palmitoyltransferase - metabolism Fatty Acids - chemistry Neovascularization, Pathologic - metabolism Human Umbilical Vein Endothelial Cells - metabolism Adenosine Triphosphate - metabolism Neovascularization, Pathologic - drug therapy Glucose - metabolism Retinopathy of Prematurity - metabolism Nucleotides - chemistry Endothelial Cells - cytology Nucleotides - pharmacology Fatty Acids - metabolism Carnitine O-Palmitoyltransferase - deficiency Carnitine O-Palmitoyltransferase - genetics Endothelial Cells - metabolism Human Umbilical Vein Endothelial Cells - cytology Neovascularization, Pathologic - pathology DNA - biosynthesis Blood Vessels - pathology Blood Vessels - metabolism Oxidation-Reduction - drug effects Endothelial Cells - enzymology Deoxyribonucleotides Physiological aspects Endothelium Ulrike Bruning oth Rindert Missiaen oth Karla C S Queiroz oth Gitte Borgers oth Ilaria Elia oth Annalisa Zecchin oth Anna Rita Cantelmo oth Stefan Christen oth Jermaine Goveia oth Ward Heggermont oth Lucica Goddë oth Stefan Vinckier oth Paul P VanVeldhoven oth Guy Eelen oth Luc Schoonjans oth Holger Gerhardt oth Mieke Dewerchin oth Myriam Baes oth Katrien De Bock oth Bart Ghesquière oth Sophia Y Lunt oth Sarah-Maria Fendt oth Peter Carmeliet oth Enthalten in Nature London : Macmillan Publishers Limited, part of Springer Nature, 1869 520(2015), 7546, Seite 192-197 (DE-627)129292834 (DE-600)120714-3 (DE-576)014473941 0028-0836 nnns volume:520 year:2015 number:7546 pages:192-197 http://dx.doi.org/10.1038/nature14362 Volltext http://www.ncbi.nlm.nih.gov/pubmed/25830893 http://search.proquest.com/docview/1672890377 http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=4413024&tool=pmcentrez&rendertype=abstract GBV_USEFLAG_A SYSFLAG_A GBV_OLC FID-BIODIV SSG-OLC-PHY SSG-OLC-CHE SSG-OLC-MAT SSG-OLC-FOR SSG-OLC-SPO SSG-OLC-PHA SSG-OLC-DE-84 SSG-OPC-FOR GBV_ILN_11 GBV_ILN_21 GBV_ILN_22 GBV_ILN_30 GBV_ILN_40 GBV_ILN_47 GBV_ILN_55 GBV_ILN_59 GBV_ILN_60 GBV_ILN_62 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_100 GBV_ILN_101 GBV_ILN_110 GBV_ILN_120 GBV_ILN_154 GBV_ILN_160 GBV_ILN_168 GBV_ILN_170 GBV_ILN_171 GBV_ILN_211 GBV_ILN_267 GBV_ILN_290 GBV_ILN_294 GBV_ILN_601 GBV_ILN_647 GBV_ILN_754 GBV_ILN_2001 GBV_ILN_2002 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2015 GBV_ILN_2016 GBV_ILN_2018 GBV_ILN_2020 GBV_ILN_2026 GBV_ILN_2095 GBV_ILN_2116 GBV_ILN_2120 GBV_ILN_2121 GBV_ILN_2173 GBV_ILN_2219 GBV_ILN_2221 GBV_ILN_2279 GBV_ILN_2286 GBV_ILN_4012 GBV_ILN_4035 GBV_ILN_4046 GBV_ILN_4125 GBV_ILN_4219 GBV_ILN_4251 GBV_ILN_4277 GBV_ILN_4302 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4313 GBV_ILN_4314 GBV_ILN_4317 GBV_ILN_4320 GBV_ILN_4324 GBV_ILN_4700 AR 520 2015 7546 192-197 |
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10.1038/nature14362 doi PQ20160617 (DE-627)OLC1962479145 (DE-599)GBVOLC1962479145 (PRQ)c3491-613c8b29dccc6cba09e995b642948eeba97aad6fa3c43a40626da0200ba90df00 (KEY)0072945020150000520754600192fattyacidcarbonisessentialfordntpsynthesisinendoth DE-627 ger DE-627 rakwb eng 070 500 DNB 500 AVZ BIODIV fid Sandra Schoors verfasserin aut Fatty acid carbon is essential for dNTP synthesis in endothelial cells 2015 Text txt rdacontent ohne Hilfsmittel zu benutzen n rdamedia Band nc rdacarrier The metabolism of endothelial cells during vessel sprouting remains poorly studied. Here we report that endothelial loss of CPT1A, a rate-limiting enzyme of fatty acid oxidation (FAO), causes vascular sprouting defects due to impaired proliferation, not migration, of human and murine endothelial cells. Reduction of FAO in endothelial cells did not cause energy depletion or disturb redox homeostasis, but impaired de novo nucleotide synthesis for DNA replication. Isotope labelling studies in control endothelial cells showed that fatty acid carbons substantially replenished the Krebs cycle, and were incorporated into aspartate (a nucleotide precursor), uridine monophosphate (a precursor of pyrimidine nucleoside triphosphates) and DNA. CPT1A silencing reduced these processes and depleted endothelial cell stores of aspartate and deoxyribonucleoside triphosphates. Acetate (metabolized to acetyl-CoA, thereby substituting for the depleted FAO-derived acetyl-CoA) or a nucleoside mix rescued the phenotype of CPT1A-silenced endothelial cells. Finally, CPT1 blockade inhibited pathological ocular angiogenesis in mice, suggesting a novel strategy for blocking angiogenesis. Kinases Protein synthesis Carbon Cells Fatty acids Angiogenesis Deoxyribonucleic acid--DNA Glucose Proteins Retinopathy of Prematurity - pathology Endothelial Cells - drug effects Carbon - metabolism Acetic Acid - pharmacology Human Umbilical Vein Endothelial Cells - drug effects Blood Vessels - drug effects Retinopathy of Prematurity - drug therapy Blood Vessels - cytology Nucleotides - biosynthesis Human Umbilical Vein Endothelial Cells - pathology Cell Proliferation - drug effects Carnitine O-Palmitoyltransferase - antagonists & inhibitors Carnitine O-Palmitoyltransferase - metabolism Fatty Acids - chemistry Neovascularization, Pathologic - metabolism Human Umbilical Vein Endothelial Cells - metabolism Adenosine Triphosphate - metabolism Neovascularization, Pathologic - drug therapy Glucose - metabolism Retinopathy of Prematurity - metabolism Nucleotides - chemistry Endothelial Cells - cytology Nucleotides - pharmacology Fatty Acids - metabolism Carnitine O-Palmitoyltransferase - deficiency Carnitine O-Palmitoyltransferase - genetics Endothelial Cells - metabolism Human Umbilical Vein Endothelial Cells - cytology Neovascularization, Pathologic - pathology DNA - biosynthesis Blood Vessels - pathology Blood Vessels - metabolism Oxidation-Reduction - drug effects Endothelial Cells - enzymology Deoxyribonucleotides Physiological aspects Endothelium Ulrike Bruning oth Rindert Missiaen oth Karla C S Queiroz oth Gitte Borgers oth Ilaria Elia oth Annalisa Zecchin oth Anna Rita Cantelmo oth Stefan Christen oth Jermaine Goveia oth Ward Heggermont oth Lucica Goddë oth Stefan Vinckier oth Paul P VanVeldhoven oth Guy Eelen oth Luc Schoonjans oth Holger Gerhardt oth Mieke Dewerchin oth Myriam Baes oth Katrien De Bock oth Bart Ghesquière oth Sophia Y Lunt oth Sarah-Maria Fendt oth Peter Carmeliet oth Enthalten in Nature London : Macmillan Publishers Limited, part of Springer Nature, 1869 520(2015), 7546, Seite 192-197 (DE-627)129292834 (DE-600)120714-3 (DE-576)014473941 0028-0836 nnns volume:520 year:2015 number:7546 pages:192-197 http://dx.doi.org/10.1038/nature14362 Volltext http://www.ncbi.nlm.nih.gov/pubmed/25830893 http://search.proquest.com/docview/1672890377 http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=4413024&tool=pmcentrez&rendertype=abstract GBV_USEFLAG_A SYSFLAG_A GBV_OLC FID-BIODIV SSG-OLC-PHY SSG-OLC-CHE SSG-OLC-MAT SSG-OLC-FOR SSG-OLC-SPO SSG-OLC-PHA SSG-OLC-DE-84 SSG-OPC-FOR GBV_ILN_11 GBV_ILN_21 GBV_ILN_22 GBV_ILN_30 GBV_ILN_40 GBV_ILN_47 GBV_ILN_55 GBV_ILN_59 GBV_ILN_60 GBV_ILN_62 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_100 GBV_ILN_101 GBV_ILN_110 GBV_ILN_120 GBV_ILN_154 GBV_ILN_160 GBV_ILN_168 GBV_ILN_170 GBV_ILN_171 GBV_ILN_211 GBV_ILN_267 GBV_ILN_290 GBV_ILN_294 GBV_ILN_601 GBV_ILN_647 GBV_ILN_754 GBV_ILN_2001 GBV_ILN_2002 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2015 GBV_ILN_2016 GBV_ILN_2018 GBV_ILN_2020 GBV_ILN_2026 GBV_ILN_2095 GBV_ILN_2116 GBV_ILN_2120 GBV_ILN_2121 GBV_ILN_2173 GBV_ILN_2219 GBV_ILN_2221 GBV_ILN_2279 GBV_ILN_2286 GBV_ILN_4012 GBV_ILN_4035 GBV_ILN_4046 GBV_ILN_4125 GBV_ILN_4219 GBV_ILN_4251 GBV_ILN_4277 GBV_ILN_4302 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4313 GBV_ILN_4314 GBV_ILN_4317 GBV_ILN_4320 GBV_ILN_4324 GBV_ILN_4700 AR 520 2015 7546 192-197 |
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Sandra Schoors @@aut@@ Ulrike Bruning @@oth@@ Rindert Missiaen @@oth@@ Karla C S Queiroz @@oth@@ Gitte Borgers @@oth@@ Ilaria Elia @@oth@@ Annalisa Zecchin @@oth@@ Anna Rita Cantelmo @@oth@@ Stefan Christen @@oth@@ Jermaine Goveia @@oth@@ Ward Heggermont @@oth@@ Lucica Goddë @@oth@@ Stefan Vinckier @@oth@@ Paul P VanVeldhoven @@oth@@ Guy Eelen @@oth@@ Luc Schoonjans @@oth@@ Holger Gerhardt @@oth@@ Mieke Dewerchin @@oth@@ Myriam Baes @@oth@@ Katrien De Bock @@oth@@ Bart Ghesquière @@oth@@ Sophia Y Lunt @@oth@@ Sarah-Maria Fendt @@oth@@ Peter Carmeliet @@oth@@ |
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Here we report that endothelial loss of CPT1A, a rate-limiting enzyme of fatty acid oxidation (FAO), causes vascular sprouting defects due to impaired proliferation, not migration, of human and murine endothelial cells. Reduction of FAO in endothelial cells did not cause energy depletion or disturb redox homeostasis, but impaired de novo nucleotide synthesis for DNA replication. Isotope labelling studies in control endothelial cells showed that fatty acid carbons substantially replenished the Krebs cycle, and were incorporated into aspartate (a nucleotide precursor), uridine monophosphate (a precursor of pyrimidine nucleoside triphosphates) and DNA. CPT1A silencing reduced these processes and depleted endothelial cell stores of aspartate and deoxyribonucleoside triphosphates. Acetate (metabolized to acetyl-CoA, thereby substituting for the depleted FAO-derived acetyl-CoA) or a nucleoside mix rescued the phenotype of CPT1A-silenced endothelial cells. 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|
| author |
Sandra Schoors |
| spellingShingle |
Sandra Schoors ddc 070 ddc 500 fid BIODIV misc Kinases misc Protein synthesis misc Carbon misc Cells misc Fatty acids misc Angiogenesis misc Deoxyribonucleic acid--DNA misc Glucose misc Proteins misc Retinopathy of Prematurity - pathology misc Endothelial Cells - drug effects misc Carbon - metabolism misc Acetic Acid - pharmacology misc Human Umbilical Vein Endothelial Cells - drug effects misc Blood Vessels - drug effects misc Retinopathy of Prematurity - drug therapy misc Blood Vessels - cytology misc Nucleotides - biosynthesis misc Human Umbilical Vein Endothelial Cells - pathology misc Cell Proliferation - drug effects misc Carnitine O-Palmitoyltransferase - antagonists & inhibitors misc Carnitine O-Palmitoyltransferase - metabolism misc Fatty Acids - chemistry misc Neovascularization, Pathologic - metabolism misc Human Umbilical Vein Endothelial Cells - metabolism misc Adenosine Triphosphate - metabolism misc Neovascularization, Pathologic - drug therapy misc Glucose - metabolism misc Retinopathy of Prematurity - metabolism misc Nucleotides - chemistry misc Endothelial Cells - cytology misc Nucleotides - pharmacology misc Fatty Acids - metabolism misc Carnitine O-Palmitoyltransferase - deficiency misc Carnitine O-Palmitoyltransferase - genetics misc Endothelial Cells - metabolism misc Human Umbilical Vein Endothelial Cells - cytology misc Neovascularization, Pathologic - pathology misc DNA - biosynthesis misc Blood Vessels - pathology misc Blood Vessels - metabolism misc Oxidation-Reduction - drug effects misc Endothelial Cells - enzymology misc Deoxyribonucleotides misc Physiological aspects misc Endothelium Fatty acid carbon is essential for dNTP synthesis in endothelial cells |
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Sandra Schoors |
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Article |
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070 - News media, journalism & publishing 500 - Natural sciences & mathematics |
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0028-0836 |
| topic_title |
070 500 DNB 500 AVZ BIODIV fid Fatty acid carbon is essential for dNTP synthesis in endothelial cells Kinases Protein synthesis Carbon Cells Fatty acids Angiogenesis Deoxyribonucleic acid--DNA Glucose Proteins Retinopathy of Prematurity - pathology Endothelial Cells - drug effects Carbon - metabolism Acetic Acid - pharmacology Human Umbilical Vein Endothelial Cells - drug effects Blood Vessels - drug effects Retinopathy of Prematurity - drug therapy Blood Vessels - cytology Nucleotides - biosynthesis Human Umbilical Vein Endothelial Cells - pathology Cell Proliferation - drug effects Carnitine O-Palmitoyltransferase - antagonists & inhibitors Carnitine O-Palmitoyltransferase - metabolism Fatty Acids - chemistry Neovascularization, Pathologic - metabolism Human Umbilical Vein Endothelial Cells - metabolism Adenosine Triphosphate - metabolism Neovascularization, Pathologic - drug therapy Glucose - metabolism Retinopathy of Prematurity - metabolism Nucleotides - chemistry Endothelial Cells - cytology Nucleotides - pharmacology Fatty Acids - metabolism Carnitine O-Palmitoyltransferase - deficiency Carnitine O-Palmitoyltransferase - genetics Endothelial Cells - metabolism Human Umbilical Vein Endothelial Cells - cytology Neovascularization, Pathologic - pathology DNA - biosynthesis Blood Vessels - pathology Blood Vessels - metabolism Oxidation-Reduction - drug effects Endothelial Cells - enzymology Deoxyribonucleotides Physiological aspects Endothelium |
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Fatty acid carbon is essential for dNTP synthesis in endothelial cells |
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Fatty acid carbon is essential for dNTP synthesis in endothelial cells |
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The metabolism of endothelial cells during vessel sprouting remains poorly studied. Here we report that endothelial loss of CPT1A, a rate-limiting enzyme of fatty acid oxidation (FAO), causes vascular sprouting defects due to impaired proliferation, not migration, of human and murine endothelial cells. Reduction of FAO in endothelial cells did not cause energy depletion or disturb redox homeostasis, but impaired de novo nucleotide synthesis for DNA replication. Isotope labelling studies in control endothelial cells showed that fatty acid carbons substantially replenished the Krebs cycle, and were incorporated into aspartate (a nucleotide precursor), uridine monophosphate (a precursor of pyrimidine nucleoside triphosphates) and DNA. CPT1A silencing reduced these processes and depleted endothelial cell stores of aspartate and deoxyribonucleoside triphosphates. Acetate (metabolized to acetyl-CoA, thereby substituting for the depleted FAO-derived acetyl-CoA) or a nucleoside mix rescued the phenotype of CPT1A-silenced endothelial cells. Finally, CPT1 blockade inhibited pathological ocular angiogenesis in mice, suggesting a novel strategy for blocking angiogenesis. |
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The metabolism of endothelial cells during vessel sprouting remains poorly studied. Here we report that endothelial loss of CPT1A, a rate-limiting enzyme of fatty acid oxidation (FAO), causes vascular sprouting defects due to impaired proliferation, not migration, of human and murine endothelial cells. Reduction of FAO in endothelial cells did not cause energy depletion or disturb redox homeostasis, but impaired de novo nucleotide synthesis for DNA replication. Isotope labelling studies in control endothelial cells showed that fatty acid carbons substantially replenished the Krebs cycle, and were incorporated into aspartate (a nucleotide precursor), uridine monophosphate (a precursor of pyrimidine nucleoside triphosphates) and DNA. CPT1A silencing reduced these processes and depleted endothelial cell stores of aspartate and deoxyribonucleoside triphosphates. Acetate (metabolized to acetyl-CoA, thereby substituting for the depleted FAO-derived acetyl-CoA) or a nucleoside mix rescued the phenotype of CPT1A-silenced endothelial cells. Finally, CPT1 blockade inhibited pathological ocular angiogenesis in mice, suggesting a novel strategy for blocking angiogenesis. |
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The metabolism of endothelial cells during vessel sprouting remains poorly studied. Here we report that endothelial loss of CPT1A, a rate-limiting enzyme of fatty acid oxidation (FAO), causes vascular sprouting defects due to impaired proliferation, not migration, of human and murine endothelial cells. Reduction of FAO in endothelial cells did not cause energy depletion or disturb redox homeostasis, but impaired de novo nucleotide synthesis for DNA replication. Isotope labelling studies in control endothelial cells showed that fatty acid carbons substantially replenished the Krebs cycle, and were incorporated into aspartate (a nucleotide precursor), uridine monophosphate (a precursor of pyrimidine nucleoside triphosphates) and DNA. CPT1A silencing reduced these processes and depleted endothelial cell stores of aspartate and deoxyribonucleoside triphosphates. Acetate (metabolized to acetyl-CoA, thereby substituting for the depleted FAO-derived acetyl-CoA) or a nucleoside mix rescued the phenotype of CPT1A-silenced endothelial cells. Finally, CPT1 blockade inhibited pathological ocular angiogenesis in mice, suggesting a novel strategy for blocking angiogenesis. |
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