title: Convergence of Notch and beta-catenin signaling induces arterial fate in vascular progenitors.
abstract: Molecular mechanisms controlling arterial-venous specification have not been fully elucidated. Previously, we established an embryonic stem cell differentiation system and demonstrated that activation of cAMP signaling together with VEGF induces arterial endothelial cells (ECs) from Flk1(+) vascular progenitor cells. Here, we show novel arterial specification machinery regulated by Notch and beta-catenin signaling. Notch and GSK3beta-mediated beta-catenin signaling were activated downstream of cAMP through phosphatidylinositol-3 kinase. Forced activation of Notch and beta-catenin with VEGF completely reconstituted cAMP-elicited arterial EC induction, and synergistically enhanced target gene promoter activity in vitro and arterial gene expression during in vivo angiogenesis. A protein complex with RBP-J, the intracellular domain of Notch, and beta-catenin was formed on RBP-J binding sites of arterial genes in arterial, but not venous ECs. This molecular machinery for arterial specification leads to an integrated and more comprehensive understanding of vascular signaling.
authors.affiliation: Laboratory of Stem Cell Differentiation, Stem Cell Research Center, Institute for Frontier Medical Sciences, Kyoto University, Kyoto 606-8507, Japan.
authors.forename: Kohei
authors.initials: K
authors.lastname: Yamamizu
authors.forename: Taichi
authors.initials: T
authors.lastname: Matsunaga
authors.forename: Hideki
authors.initials: H
authors.lastname: Uosaki
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Fukushima
authors.forename: Shiori
authors.initials: S
authors.lastname: Katayama
authors.forename: Mina
authors.initials: M
authors.lastname: Hiraoka-Kanie
authors.forename: Kohnosuke
authors.initials: K
authors.lastname: Mitani
authors.forename: Jun K
authors.initials: JK
authors.lastname: Yamashita
mesh_terms: D000818:Animals; D001158:Arteries / Q000166:cytology / Q000196:embryology* / Q000378:metabolism; D015415:Biomarkers / Q000378:metabolism; D002454:Cell Differentiation / Q000502:physiology; D000242:Cyclic AMP / Q000378:metabolism; D042783:Endothelial Cells / Q000166:cytology / Q000502:physiology*; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018919:Neovascularization, Physiologic / Q000502:physiology; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D013234:Stem Cells / Q000166:cytology / Q000502:physiology*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics / Q000378:metabolism; D014680:Veins / Q000166:cytology / Q000196:embryology / Q000378:metabolism; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
chemical_list: D015415:Biomarkers; D000242:Cyclic AMP; D038362:Glycogen Synthase Kinase 3; D000071679:Glycogen Synthase Kinase 3 beta; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051880:Receptors, Notch; D042461:Vascular Endothelial Growth Factor A; D040301:Vascular Endothelial Growth Factor Receptor-2; D051176:beta Catenin; C497571:Rbpj protein, mouse; C000605507:Gsk3b protein, mouse
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