title: FGF-dependent regulation of VEGF receptor 2 expression in mice.
abstract: Numerous studies have suggested a link between the angiogenic FGF and VEGF signaling pathways; however, the nature of this link has not been established. To evaluate this relationship, we investigated VEGF signaling in ECs with disrupted FGF signaling in vitro and in vivo. ECs lacking FGF signaling became unresponsive to VEGF, caused by downregulation of VEGF receptor 2 (VEGFR2) expression after reduced Vegfr2 enhancer activation. FGF mediated VEGFR2 expression via activation of Erk1/2. Transcriptional analysis revealed that Ets transcription factors controlled VEGFR2 expression in an FGF- and Erk1/2-dependent manner. Mice with defective FGF signaling exhibited loss of vascular integrity and reduced vascular morphogenesis. Thus, basal FGF stimulation of the endothelium is required for maintenance of VEGFR2 expression and the ability to respond to VEGF stimulation and accounts for the hierarchic control of vascular formation by FGFs and VEGF.
authors.affiliation: Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Murakami
authors.forename: Loc T
authors.initials: LT
authors.lastname: Nguyen
authors.forename: Kunihiko
authors.initials: K
authors.lastname: Hatanaka
authors.forename: William
authors.initials: W
authors.lastname: Schachterle
authors.forename: Pei-Yu
authors.initials: PY
authors.lastname: Chen
authors.forename: Zhen W
authors.initials: ZW
authors.lastname: Zhuang
authors.forename: Brian L
authors.initials: BL
authors.lastname: Black
authors.forename: Michael
authors.initials: M
authors.lastname: Simons
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000166:cytology / Q000502:physiology; D004789:Enzyme Activation; D005346:Fibroblast Growth Factors / Q000235:genetics / Q000378:metabolism*; D006614:Hindlimb / Q000098:blood supply / Q000473:pathology; D006801:Humans; D007511:Ischemia / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D018919:Neovascularization, Physiologic / Q000502:physiology; D050783:Proto-Oncogene Proteins c-ets / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics / Q000378:metabolism*; D042442:Vascular Endothelial Growth Factors / Q000378:metabolism*
chemical_list: D050783:Proto-Oncogene Proteins c-ets; D042442:Vascular Endothelial Growth Factors; D005346:Fibroblast Growth Factors; D040301:Vascular Endothelial Growth Factor Receptor-2; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3