title: SoxF Transcription Factors Are Positive Feedback Regulators of VEGF Signaling.
abstract: BACKGROUND
  Vascular endothelial growth factor (VEGF) signaling is a key pathway for angiogenesis and requires highly coordinated regulation. Although the Notch pathway-mediated suppression of excessive VEGF activity via negative feedback is well known, the positive feedback control for augmenting VEGF signaling remains poorly understood. Transcription factor Sox17 is indispensable for angiogenesis, but its association with VEGF signaling is largely unknown. The contribution of other Sox members to angiogenesis also remains to be determined.
  
  
  OBJECTIVE
  To reveal the genetic interaction of Sox7, another Sox member, with Sox17 in developmental angiogenesis and their functional relationship with VEGF signaling.
  
  
  RESULTS
  Sox7 is expressed specifically in endothelial cells and its global and endothelial-specific deletion resulted in embryonic lethality with severely impaired angiogenesis in mice, substantially overlapping with Sox17 in both expression and function. Interestingly, compound heterozygosity for Sox7 and Sox17 phenocopied vascular defects of Sox7 or Sox17 homozygous knockout, indicating that the genetic cooperation of Sox7 and Sox17 is sensitive to their combined gene dosage. VEGF signaling upregulated both Sox7 and Sox17 expression in angiogenesis via mTOR pathway. Furthermore, Sox7 and Sox17 promoted VEGFR2 (VEGF receptor 2) expression in angiogenic vessels, suggesting a positive feedback loop between VEGF signaling and SoxF.
  
  
  CONCLUSIONS
  Our findings demonstrate that SoxF transcription factors are indispensable players in developmental angiogenesis by acting as positive feedback regulators of VEGF signaling.
authors.affiliation: From the Department of Biological Sciences (K.K., J.W.K., G.Y.K., I.K.), Graduate School of Medical Science and Engineering (I.-K.K., J.M.Y., B.I.K., S.L., G.Y.K., I.K.), Biomedical Science and Engineering Interdisciplinary Program (E.L., G.Y.K., I.K.), and Department of Bio and Brain Engineering (J.P., C.C.), Korea Advanced Institute of Science and Technology, Daejeon; Center for Vascular Research, Institute for Basic Science, Daejeon, Republic of Korea (K.K., S.S., G.Y.K.); Department of Otolaryngology-Head and Neck Surgery, Chonnam National University Hospital, Gwangju, Republic of Korea (S.L.); and The Laboratory of Vascular Biology, Keio University, Tokyo, Japan (Y.K.).
authors.forename: Kangsan
authors.initials: K
authors.lastname: Kim
authors.affiliation: From the Department of Biological Sciences (K.K., J.W.K., G.Y.K., I.K.), Graduate School of Medical Science and Engineering (I.-K.K., J.M.Y., B.I.K., S.L., G.Y.K., I.K.), Biomedical Science and Engineering Interdisciplinary Program (E.L., G.Y.K., I.K.), and Department of Bio and Brain Engineering (J.P., C.C.), Korea Advanced Institute of Science and Technology, Daejeon; Center for Vascular Research, Institute for Basic Science, Daejeon, Republic of Korea (K.K., S.S., G.Y.K.); Department of Otolaryngology-Head and Neck Surgery, Chonnam National University Hospital, Gwangju, Republic of Korea (S.L.); and The Laboratory of Vascular Biology, Keio University, Tokyo, Japan (Y.K.).
authors.forename: Il-Kug
authors.initials: IK
authors.lastname: Kim
authors.affiliation: From the Department of Biological Sciences (K.K., J.W.K., G.Y.K., I.K.), Graduate School of Medical Science and Engineering (I.-K.K., J.M.Y., B.I.K., S.L., G.Y.K., I.K.), Biomedical Science and Engineering Interdisciplinary Program (E.L., G.Y.K., I.K.), and Department of Bio and Brain Engineering (J.P., C.C.), Korea Advanced Institute of Science and Technology, Daejeon; Center for Vascular Research, Institute for Basic Science, Daejeon, Republic of Korea (K.K., S.S., G.Y.K.); Department of Otolaryngology-Head and Neck Surgery, Chonnam National University Hospital, Gwangju, Republic of Korea (S.L.); and The Laboratory of Vascular Biology, Keio University, Tokyo, Japan (Y.K.).
authors.forename: Jee Myung
authors.initials: JM
authors.lastname: Yang
authors.affiliation: From the Department of Biological Sciences (K.K., J.W.K., G.Y.K., I.K.), Graduate School of Medical Science and Engineering (I.-K.K., J.M.Y., B.I.K., S.L., G.Y.K., I.K.), Biomedical Science and Engineering Interdisciplinary Program (E.L., G.Y.K., I.K.), and Department of Bio and Brain Engineering (J.P., C.C.), Korea Advanced Institute of Science and Technology, Daejeon; Center for Vascular Research, Institute for Basic Science, Daejeon, Republic of Korea (K.K., S.S., G.Y.K.); Department of Otolaryngology-Head and Neck Surgery, Chonnam National University Hospital, Gwangju, Republic of Korea (S.L.); and The Laboratory of Vascular Biology, Keio University, Tokyo, Japan (Y.K.).
authors.forename: Eunhyeong
authors.initials: E
authors.lastname: Lee
authors.affiliation: From the Department of Biological Sciences (K.K., J.W.K., G.Y.K., I.K.), Graduate School of Medical Science and Engineering (I.-K.K., J.M.Y., B.I.K., S.L., G.Y.K., I.K.), Biomedical Science and Engineering Interdisciplinary Program (E.L., G.Y.K., I.K.), and Department of Bio and Brain Engineering (J.P., C.C.), Korea Advanced Institute of Science and Technology, Daejeon; Center for Vascular Research, Institute for Basic Science, Daejeon, Republic of Korea (K.K., S.S., G.Y.K.); Department of Otolaryngology-Head and Neck Surgery, Chonnam National University Hospital, Gwangju, Republic of Korea (S.L.); and The Laboratory of Vascular Biology, Keio University, Tokyo, Japan (Y.K.).
authors.forename: Bong Ihn
authors.initials: BI
authors.lastname: Koh
authors.affiliation: From the Department of Biological Sciences (K.K., J.W.K., G.Y.K., I.K.), Graduate School of Medical Science and Engineering (I.-K.K., J.M.Y., B.I.K., S.L., G.Y.K., I.K.), Biomedical Science and Engineering Interdisciplinary Program (E.L., G.Y.K., I.K.), and Department of Bio and Brain Engineering (J.P., C.C.), Korea Advanced Institute of Science and Technology, Daejeon; Center for Vascular Research, Institute for Basic Science, Daejeon, Republic of Korea (K.K., S.S., G.Y.K.); Department of Otolaryngology-Head and Neck Surgery, Chonnam National University Hospital, Gwangju, Republic of Korea (S.L.); and The Laboratory of Vascular Biology, Keio University, Tokyo, Japan (Y.K.).
authors.forename: Sukhyun
authors.initials: S
authors.lastname: Song
authors.affiliation: From the Department of Biological Sciences (K.K., J.W.K., G.Y.K., I.K.), Graduate School of Medical Science and Engineering (I.-K.K., J.M.Y., B.I.K., S.L., G.Y.K., I.K.), Biomedical Science and Engineering Interdisciplinary Program (E.L., G.Y.K., I.K.), and Department of Bio and Brain Engineering (J.P., C.C.), Korea Advanced Institute of Science and Technology, Daejeon; Center for Vascular Research, Institute for Basic Science, Daejeon, Republic of Korea (K.K., S.S., G.Y.K.); Department of Otolaryngology-Head and Neck Surgery, Chonnam National University Hospital, Gwangju, Republic of Korea (S.L.); and The Laboratory of Vascular Biology, Keio University, Tokyo, Japan (Y.K.).
authors.forename: Junseong
authors.initials: J
authors.lastname: Park
authors.affiliation: From the Department of Biological Sciences (K.K., J.W.K., G.Y.K., I.K.), Graduate School of Medical Science and Engineering (I.-K.K., J.M.Y., B.I.K., S.L., G.Y.K., I.K.), Biomedical Science and Engineering Interdisciplinary Program (E.L., G.Y.K., I.K.), and Department of Bio and Brain Engineering (J.P., C.C.), Korea Advanced Institute of Science and Technology, Daejeon; Center for Vascular Research, Institute for Basic Science, Daejeon, Republic of Korea (K.K., S.S., G.Y.K.); Department of Otolaryngology-Head and Neck Surgery, Chonnam National University Hospital, Gwangju, Republic of Korea (S.L.); and The Laboratory of Vascular Biology, Keio University, Tokyo, Japan (Y.K.).
authors.forename: Sungsu
authors.initials: S
authors.lastname: Lee
authors.affiliation: From the Department of Biological Sciences (K.K., J.W.K., G.Y.K., I.K.), Graduate School of Medical Science and Engineering (I.-K.K., J.M.Y., B.I.K., S.L., G.Y.K., I.K.), Biomedical Science and Engineering Interdisciplinary Program (E.L., G.Y.K., I.K.), and Department of Bio and Brain Engineering (J.P., C.C.), Korea Advanced Institute of Science and Technology, Daejeon; Center for Vascular Research, Institute for Basic Science, Daejeon, Republic of Korea (K.K., S.S., G.Y.K.); Department of Otolaryngology-Head and Neck Surgery, Chonnam National University Hospital, Gwangju, Republic of Korea (S.L.); and The Laboratory of Vascular Biology, Keio University, Tokyo, Japan (Y.K.).
authors.forename: Chulhee
authors.initials: C
authors.lastname: Choi
authors.affiliation: From the Department of Biological Sciences (K.K., J.W.K., G.Y.K., I.K.), Graduate School of Medical Science and Engineering (I.-K.K., J.M.Y., B.I.K., S.L., G.Y.K., I.K.), Biomedical Science and Engineering Interdisciplinary Program (E.L., G.Y.K., I.K.), and Department of Bio and Brain Engineering (J.P., C.C.), Korea Advanced Institute of Science and Technology, Daejeon; Center for Vascular Research, Institute for Basic Science, Daejeon, Republic of Korea (K.K., S.S., G.Y.K.); Department of Otolaryngology-Head and Neck Surgery, Chonnam National University Hospital, Gwangju, Republic of Korea (S.L.); and The Laboratory of Vascular Biology, Keio University, Tokyo, Japan (Y.K.).
authors.forename: Jin Woo
authors.initials: JW
authors.lastname: Kim
authors.affiliation: From the Department of Biological Sciences (K.K., J.W.K., G.Y.K., I.K.), Graduate School of Medical Science and Engineering (I.-K.K., J.M.Y., B.I.K., S.L., G.Y.K., I.K.), Biomedical Science and Engineering Interdisciplinary Program (E.L., G.Y.K., I.K.), and Department of Bio and Brain Engineering (J.P., C.C.), Korea Advanced Institute of Science and Technology, Daejeon; Center for Vascular Research, Institute for Basic Science, Daejeon, Republic of Korea (K.K., S.S., G.Y.K.); Department of Otolaryngology-Head and Neck Surgery, Chonnam National University Hospital, Gwangju, Republic of Korea (S.L.); and The Laboratory of Vascular Biology, Keio University, Tokyo, Japan (Y.K.).
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Kubota
authors.affiliation: From the Department of Biological Sciences (K.K., J.W.K., G.Y.K., I.K.), Graduate School of Medical Science and Engineering (I.-K.K., J.M.Y., B.I.K., S.L., G.Y.K., I.K.), Biomedical Science and Engineering Interdisciplinary Program (E.L., G.Y.K., I.K.), and Department of Bio and Brain Engineering (J.P., C.C.), Korea Advanced Institute of Science and Technology, Daejeon; Center for Vascular Research, Institute for Basic Science, Daejeon, Republic of Korea (K.K., S.S., G.Y.K.); Department of Otolaryngology-Head and Neck Surgery, Chonnam National University Hospital, Gwangju, Republic of Korea (S.L.); and The Laboratory of Vascular Biology, Keio University, Tokyo, Japan (Y.K.).
authors.forename: Gou Young
authors.initials: GY
authors.lastname: Koh
authors.affiliation: From the Department of Biological Sciences (K.K., J.W.K., G.Y.K., I.K.), Graduate School of Medical Science and Engineering (I.-K.K., J.M.Y., B.I.K., S.L., G.Y.K., I.K.), Biomedical Science and Engineering Interdisciplinary Program (E.L., G.Y.K., I.K.), and Department of Bio and Brain Engineering (J.P., C.C.), Korea Advanced Institute of Science and Technology, Daejeon; Center for Vascular Research, Institute for Basic Science, Daejeon, Republic of Korea (K.K., S.S., G.Y.K.); Department of Otolaryngology-Head and Neck Surgery, Chonnam National University Hospital, Gwangju, Republic of Korea (S.L.); and The Laboratory of Vascular Biology, Keio University, Tokyo, Japan (Y.K.). injunek@kaist.ac.kr.
authors.forename: Injune
authors.initials: I
authors.lastname: Kim
mesh_terms: D000818:Animals; D046508:Culture Techniques; D005260:Female; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism*; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D018919:Neovascularization, Physiologic / Q000502:physiology*; D011247:Pregnancy; D055760:SOXF Transcription Factors / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
chemical_list: D055760:SOXF Transcription Factors; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse
keywords: SoxF transcription factors; endothelial cells; physiologic angiogenesis; physiological feedback; vascular endothelial growth factor A