title: Fatty acid-binding protein 4, a point of convergence for angiogenic and metabolic signaling pathways in endothelial cells.
abstract: Fatty acid-binding protein 4 (FABP4) is an adipogenic protein and is implicated in atherosclerosis, insulin resistance, and cancer. In endothelial cells, FABP4 is induced by VEGFA, and inhibition of FABP4 blocks most of the VEGFA effects. We investigated the DLL4-NOTCH-dependent regulation of FABP4 in human umbilical vein endothelial cells by gene/protein expression and interaction analyses following inhibitor treatment and RNA interference. We found that FABP4 is directly induced by NOTCH. Stimulation of NOTCH signaling with human recombinant DLL4 led to FABP4 induction, independently of VEGFA. FABP4 induction by VEGFA was reduced by blockade of DLL4 binding to NOTCH or inhibition of NOTCH signal transduction. Chromatin immunoprecipitation of the NOTCH intracellular domain showed increased binding to two specific regions in the FABP4 promoter. The induction of FABP4 gene expression was dependent on the transcription factor FOXO1, which was essential for basal expression of FABP4, and FABP4 up-regulation following stimulation of the VEGFA and/or the NOTCH pathway. Thus, we show that the DLL4-NOTCH pathway mediates endothelial FABP4 expression. This indicates that induction of the angiogenesis-restricting DLL4-NOTCH can have pro-angiogenic effects via this pathway. It also provides a link between DLL4-NOTCH and FOXO1-mediated regulation of endothelial gene transcription, and it shows that DLL4-NOTCH is a nodal point in the integration of pro-angiogenic and metabolic signaling in endothelial cells. This may be crucial for angiogenesis in the tumor environment.
authors.affiliation: Weatherall Institute of Molecular Medicine, Department of Oncology, University of Oxford, OX3 9DS Oxford.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Harjes
authors.affiliation: Weatherall Institute of Molecular Medicine, Department of Oncology, University of Oxford, OX3 9DS Oxford.
authors.forename: Esther
authors.initials: E
authors.lastname: Bridges
authors.affiliation: Weatherall Institute of Molecular Medicine, Department of Oncology, University of Oxford, OX3 9DS Oxford.
authors.forename: Alan
authors.initials: A
authors.lastname: McIntyre
authors.affiliation: Centre for Diabetes, Endocrinology and Metabolism, Churchill Hospital, Oxford OX3 7LJ, and; Department of Nutritional Sciences, University of Surrey, GU2 7WG Surrey, United Kingdom.
authors.forename: Barbara A
authors.initials: BA
authors.lastname: Fielding
authors.affiliation: Weatherall Institute of Molecular Medicine, Department of Oncology, University of Oxford, OX3 9DS Oxford,. Electronic address: aharris.lab@imm.ox.ac.uk.
authors.forename: Adrian L
authors.initials: AL
authors.lastname: Harris
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D002135:Calcium-Binding Proteins; D050556:Fatty Acid-Binding Proteins / Q000096:biosynthesis* / Q000235:genetics; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000502:physiology*; D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D009369:Neoplasms / Q000098:blood supply / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D018919:Neovascularization, Physiologic / Q000502:physiology*; D011401:Promoter Regions, Genetic / Q000502:physiology; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002135:Calcium-Binding Proteins; C424126:DLL4 protein, human; C493410:FABP4 protein, human; C085126:FOXO1 protein, human; D050556:Fatty Acid-Binding Proteins; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D036341:Intercellular Signaling Peptides and Proteins; D009363:Neoplasm Proteins; D051880:Receptors, Notch; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A
keywords: Angiogenesis; DLL4; Endothelial Cell; FOXO; Fatty Acid-binding Protein; Metabolism; Notch Pathway; Vascular Endothelial Growth Factor (VEGF)