title: A novel role for vascular endothelial growth factor as an autocrine survival factor for embryonic stem cells during hypoxia.
abstract: Vascular endothelial growth factor (VEGF) is best known for its angiogenic activity on endothelial cells, but it also affects neurons, pneumocytes, and other mature cell types as well as endothelial, neural, and hematopoietic progenitors. Here, we examined its effect on pluripotential embryonic stem (ES) cells under hypoxic stress. ES cells were found to produce VEGF and to express VEGF receptor-2 and neuropilin-1 (Nrp-1), a VEGF165 isoform-specific receptor. During hypoxia, expression levels of VEGF, Flk-1, and Nrp-1 were elevated. Inhibition or targeted gene inactivation of VEGF increased ES cell apoptosis during prolonged hypoxia (48 h) by about 10-fold. The survival activity of VEGF was specific since inhibition of other growth factors (including basic fibroblast growth factor, epidermal growth factor, insulin-like growth factor, platelet-derived growth factor, and placental growth factor) had no effect. Neuropilin-1 was involved in the VEGF-survival activity since overexpression of Nrp-1 decreased hypoxia-induced apoptosis about 3-fold. The hypoxia-response element, via which hypoxia-inducible transcription factors up-regulate VEGF expression under hypoxic conditions, was critical since targeted deletion of this element in the VEGF promoter enhanced hypoxia-induced ES cell apoptosis to the same extent as VEGF inhibition or gene inactivation. Thus, VEGF plays a critical role in survival of ES cells during prolonged hypoxia.
authors.affiliation: Center for Transgene Technology and Gene Therapy, Flanders Interuniversity Institute for Biotechnology (VIB), KULeuven, Leuven, B-3000, Belgium.
authors.forename: Koen
authors.initials: K
authors.lastname: Brusselmans
authors.forename: Françoise
authors.initials: F
authors.lastname: Bono
authors.forename: Désiré
authors.initials: D
authors.lastname: Collen
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Herbert
authors.forename: Peter
authors.initials: P
authors.lastname: Carmeliet
authors.forename: Mieke
authors.initials: M
authors.lastname: Dewerchin
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D019898:Autocrine Communication / Q000502:physiology; D002470:Cell Survival / Q000502:physiology; D006801:Humans; D000860:Hypoxia / Q000378:metabolism*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009115:Muridae; D039942:Neuropilin-1 / Q000235:genetics / Q000378:metabolism; D020218:Response Elements / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D013234:Stem Cells / Q000166:cytology* / Q000502:physiology*; D014157:Transcription Factors / Q000378:metabolism; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics* / Q000378:metabolism*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics / Q000378:metabolism
chemical_list: C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A; D039942:Neuropilin-1; D040301:Vascular Endothelial Growth Factor Receptor-2