title: Notch pathway targets proangiogenic regulator Sox17 to restrict angiogenesis.
abstract: BACKGROUND
  The Notch pathway stabilizes sprouting angiogenesis by favoring stalk cells over tip cells at the vascular front. Because tip and stalk cells have different properties in morphology and function, their transcriptional regulation remains to be distinguished. Transcription factor Sox17 is specifically expressed in endothelial cells, but its expression and role at the vascular front remain largely unknown.
  
  
  OBJECTIVE
  To specify the role of Sox17 and its relationship with the Notch pathway in sprouting angiogenesis.
  
  
  RESULTS
  Endothelial-specific Sox17 deletion reduces sprouting angiogenesis in mouse embryonic and postnatal vascular development, whereas Sox17 overexpression increases it. Sox17 promotes endothelial migration by destabilizing endothelial junctions and rearranging cytoskeletal structure and upregulates expression of several genes preferentially expressed in tip cells. Interestingly, Sox17 expression is suppressed in stalk cells in which Notch signaling is relatively high. Notch activation by overexpressing Notch intracellular domain reduces Sox17 expression both in primary endothelial cells and in retinal angiogenesis, whereas Notch inhibition by delta-like ligand 4 (Dll4) blockade increases it. The Notch pathway regulates Sox17 expression mainly at the post-transcriptional level. Furthermore, endothelial Sox17 ablation rescues vascular network from excessive tip cell formation and hyperbranching under Notch inhibition in developmental and tumor angiogenesis.
  
  
  CONCLUSIONS
  Our findings demonstrate that the Notch pathway restricts sprouting angiogenesis by reducing the expression of proangiogenic regulator Sox17.
authors.affiliation: From the Graduate School of Medical Science and Engineering (S.-H.L., S.L., H.Y., S.S., K.K., G.Y.K., I.K.) and Biomedical Science and Engineering Interdisciplinary Program (S.-H.L., G.Y.K., I.K.), Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea; Department of Otolaryngology-Head and Neck Surgery, Chonnam National University Hospital, Gwangju, Republic of Korea (S.L.); Transgenic Animal Model Core, University of Michigan, Ann Arbor (T.L.S.); and Center for Molecular Medicine, Maine Medical Center Research Institute, Scarborough (J.K.Y.).
authors.forename: Seung-Hun
authors.initials: SH
authors.lastname: Lee
authors.affiliation: From the Graduate School of Medical Science and Engineering (S.-H.L., S.L., H.Y., S.S., K.K., G.Y.K., I.K.) and Biomedical Science and Engineering Interdisciplinary Program (S.-H.L., G.Y.K., I.K.), Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea; Department of Otolaryngology-Head and Neck Surgery, Chonnam National University Hospital, Gwangju, Republic of Korea (S.L.); Transgenic Animal Model Core, University of Michigan, Ann Arbor (T.L.S.); and Center for Molecular Medicine, Maine Medical Center Research Institute, Scarborough (J.K.Y.).
authors.forename: Sungsu
authors.initials: S
authors.lastname: Lee
authors.affiliation: From the Graduate School of Medical Science and Engineering (S.-H.L., S.L., H.Y., S.S., K.K., G.Y.K., I.K.) and Biomedical Science and Engineering Interdisciplinary Program (S.-H.L., G.Y.K., I.K.), Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea; Department of Otolaryngology-Head and Neck Surgery, Chonnam National University Hospital, Gwangju, Republic of Korea (S.L.); Transgenic Animal Model Core, University of Michigan, Ann Arbor (T.L.S.); and Center for Molecular Medicine, Maine Medical Center Research Institute, Scarborough (J.K.Y.).
authors.forename: Hanseul
authors.initials: H
authors.lastname: Yang
authors.affiliation: From the Graduate School of Medical Science and Engineering (S.-H.L., S.L., H.Y., S.S., K.K., G.Y.K., I.K.) and Biomedical Science and Engineering Interdisciplinary Program (S.-H.L., G.Y.K., I.K.), Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea; Department of Otolaryngology-Head and Neck Surgery, Chonnam National University Hospital, Gwangju, Republic of Korea (S.L.); Transgenic Animal Model Core, University of Michigan, Ann Arbor (T.L.S.); and Center for Molecular Medicine, Maine Medical Center Research Institute, Scarborough (J.K.Y.).
authors.forename: Sukhyun
authors.initials: S
authors.lastname: Song
authors.affiliation: From the Graduate School of Medical Science and Engineering (S.-H.L., S.L., H.Y., S.S., K.K., G.Y.K., I.K.) and Biomedical Science and Engineering Interdisciplinary Program (S.-H.L., G.Y.K., I.K.), Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea; Department of Otolaryngology-Head and Neck Surgery, Chonnam National University Hospital, Gwangju, Republic of Korea (S.L.); Transgenic Animal Model Core, University of Michigan, Ann Arbor (T.L.S.); and Center for Molecular Medicine, Maine Medical Center Research Institute, Scarborough (J.K.Y.).
authors.forename: Kangsan
authors.initials: K
authors.lastname: Kim
authors.affiliation: From the Graduate School of Medical Science and Engineering (S.-H.L., S.L., H.Y., S.S., K.K., G.Y.K., I.K.) and Biomedical Science and Engineering Interdisciplinary Program (S.-H.L., G.Y.K., I.K.), Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea; Department of Otolaryngology-Head and Neck Surgery, Chonnam National University Hospital, Gwangju, Republic of Korea (S.L.); Transgenic Animal Model Core, University of Michigan, Ann Arbor (T.L.S.); and Center for Molecular Medicine, Maine Medical Center Research Institute, Scarborough (J.K.Y.).
authors.forename: Thomas L
authors.initials: TL
authors.lastname: Saunders
authors.affiliation: From the Graduate School of Medical Science and Engineering (S.-H.L., S.L., H.Y., S.S., K.K., G.Y.K., I.K.) and Biomedical Science and Engineering Interdisciplinary Program (S.-H.L., G.Y.K., I.K.), Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea; Department of Otolaryngology-Head and Neck Surgery, Chonnam National University Hospital, Gwangju, Republic of Korea (S.L.); Transgenic Animal Model Core, University of Michigan, Ann Arbor (T.L.S.); and Center for Molecular Medicine, Maine Medical Center Research Institute, Scarborough (J.K.Y.).
authors.forename: Jeong K
authors.initials: JK
authors.lastname: Yoon
authors.affiliation: From the Graduate School of Medical Science and Engineering (S.-H.L., S.L., H.Y., S.S., K.K., G.Y.K., I.K.) and Biomedical Science and Engineering Interdisciplinary Program (S.-H.L., G.Y.K., I.K.), Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea; Department of Otolaryngology-Head and Neck Surgery, Chonnam National University Hospital, Gwangju, Republic of Korea (S.L.); Transgenic Animal Model Core, University of Michigan, Ann Arbor (T.L.S.); and Center for Molecular Medicine, Maine Medical Center Research Institute, Scarborough (J.K.Y.) injunek@kaist.ac.kr gykoh@kaist.ac.kr.
authors.forename: Gou Young
authors.initials: GY
authors.lastname: Koh
authors.affiliation: From the Graduate School of Medical Science and Engineering (S.-H.L., S.L., H.Y., S.S., K.K., G.Y.K., I.K.) and Biomedical Science and Engineering Interdisciplinary Program (S.-H.L., G.Y.K., I.K.), Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea; Department of Otolaryngology-Head and Neck Surgery, Chonnam National University Hospital, Gwangju, Republic of Korea (S.L.); Transgenic Animal Model Core, University of Michigan, Ann Arbor (T.L.S.); and Center for Molecular Medicine, Maine Medical Center Research Institute, Scarborough (J.K.Y.) injunek@kaist.ac.kr gykoh@kaist.ac.kr.
authors.forename: Injune
authors.initials: I
authors.lastname: Kim
mesh_terms: D000818:Animals; D018827:Carcinoma, Lewis Lung / Q000098:blood supply; D002454:Cell Differentiation; D002465:Cell Movement; D003599:Cytoskeleton / Q000648:ultrastructure; D004622:Embryo, Mammalian / Q000098:blood supply; D053595:Embryonic Stem Cells; D042783:Endothelial Cells / Q000378:metabolism*; D005786:Gene Expression Regulation; D024002:HMGB Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D007365:Intercellular Junctions / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009024:Morphogenesis / Q000235:genetics; D009389:Neovascularization, Pathologic / Q000503:physiopathology*; D018919:Neovascularization, Physiologic / Q000502:physiology*; D017434:Protein Structure, Tertiary; D034741:RNA, Small Interfering / Q000494:pharmacology; D051881:Receptor, Notch1 / Q000235:genetics / Q000502:physiology; D051880:Receptors, Notch / Q000502:physiology*; D011993:Recombinant Fusion Proteins; D012171:Retinal Vessels / Q000254:growth & development; D055760:SOXF Transcription Factors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D013047:Specific Pathogen-Free Organisms; D014158:Transcription, Genetic
chemical_list: D024002:HMGB Proteins; C497761:NOTCH1 protein, human; D034741:RNA, Small Interfering; D051881:Receptor, Notch1; D051880:Receptors, Notch; D011993:Recombinant Fusion Proteins; D055760:SOXF Transcription Factors; C511606:Sox17 protein, mouse
keywords: Notch receptors; Sox17 transcription factor; delta-like ligand 4; physiologic angiogenesis