title: NGF activation of TrkA induces vascular endothelial growth factor expression via induction of hypoxia-inducible factor-1α.
abstract: Communication between the vasculature and nervous system is important during embryogenesis but the molecular mechanisms mediating this are ill-defined. We evaluated the molecular mechanisms by which Nerve Growth Factor (NGF) and Brain-derived neurotrophic factor (BDNF) regulate VEGF production. NGF activation of TrkA causes a marked increase in VEGF secretion by neuronal cells. The NGF induced increase in VEGF is accompanied by an increase in HIF-1α. Pharmacologic inhibitors of the Trk tyrosine kinase, PI-3 kinase and mTOR paths prevent NGF stimulated increases in HIF-1α and VEGF. NGF induced increase in VEGF transcription is dependent on a hypoxia response element (HRE) in the VEGF promoter. Mutation of the HRE or siRNA mediated silencing of HIF-1α expression blocks NGF induced increases in VEGF transcription. In primary cultures of TrkA expressing neurons from dorsal root ganglion, NGF induces VEGF expression that is accompanied by increases in HIF-1α but not HIF-2α expression. In CGN neurons, BDNF induces VEGF that is dependent on induction of HIF-1α. Our study indicates that neurotrophin activation of Trk stimulates an increase in VEGF transcription that is mediated by induction of HIF-1α.
authors.affiliation: Cell & Molecular Biology Section, Pediatric Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. knakamura@kokura2.hosp.go.jp
authors.forename: Katsuya
authors.initials: K
authors.lastname: Nakamura
authors.forename: Fei
authors.initials: F
authors.lastname: Tan
authors.forename: Zhijie
authors.initials: Z
authors.lastname: Li
authors.forename: Carol J
authors.initials: CJ
authors.lastname: Thiele
mesh_terms: D000818:Animals; D015153:Blotting, Western; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D002531:Cerebellum / Q000378:metabolism; D004789:Enzyme Activation; D005727:Ganglia, Spinal / Q000378:metabolism; D015870:Gene Expression; D005786:Gene Expression Regulation / Q000235:genetics*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000096:biosynthesis*; D007150:Immunohistochemistry; D051379:Mice; D020932:Nerve Growth Factor / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D020917:Receptor, trkA / Q000235:genetics / Q000378:metabolism*; D020218:Response Elements / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D014162:Transfection; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D019208:Brain-Derived Neurotrophic Factor; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D020932:Nerve Growth Factor; D020917:Receptor, trkA