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The role of TGF-・・signaling in Angiogenesis

Research Project

Project/Area Number 21890022
Research Category

Grant-in-Aid for Research Activity Start-up

Allocation TypeSingle-year Grants
Research Field Experimental pathology
Research InstitutionUniversity of Tsukuba

Principal Investigator

ITOH Fumiko  University of Tsukuba, 大学院・人間総合科学研究科, 助教 (70502582)

Project Period (FY) 2009 – 2010
Project Status Completed (Fiscal Year 2010)
Budget Amount *help
¥2,652,000 (Direct Cost: ¥2,040,000、Indirect Cost: ¥612,000)
Fiscal Year 2010: ¥1,261,000 (Direct Cost: ¥970,000、Indirect Cost: ¥291,000)
Fiscal Year 2009: ¥1,391,000 (Direct Cost: ¥1,070,000、Indirect Cost: ¥321,000)
KeywordsTGF-・ / 血管新生 / Smad2 / 3 / conditional knockout / リンパ管 / TGF-β / Smad2/3 / LYVE-1 / N-cadherin
Research Abstract

In order to elucidate molecular mechanisms by which TGF-β/ALK5/Smad2/3 pathway regulates vascular development, we established mouse embryonic endothelial cells (MEECs) from Smad2/3 conditionally inactivated mice. When we checked the reaction against for the shear stress, the Smad2/3KO MEECs did not respond it. Then we analyzed the molecular mechanisms with mRNA and miRNA arrays analysis and found that the expression of some cadherins were reduced in Smad2/3 KO MEEC compared to the wild type MEECs.
Although TGF-β signaling is known to play key roles in angiogenesis, it remains veiled how TGF-β regulates lymphangiogenesis. To elucidate molecular mechanisms by which TGF-β pathway controls lymphatic vascular development, we conditionally inactivated TGF-β type II receptor (TβRII) in LECs using Prox1-Cre-ER transgenic mice. When we administered Tamoxifen (TM) at E10.5 and E11.5, TβRIIF/F ; Prox1-CreER embryos showed edema at E14.5. Therefore we stained blood and lymphatic vessels with anti-PECAM-1 and anti-LYVE-1 antibodies, respectively. Interestingly, blood vessel seemed to be well-established, whereas lymphatic vessels merely existed though they were ragged and poorly organized. These data indicated that TGF-β signaling is indispensable for maintenance of lymphatic vessel integrities.

Report

(3 results)
  • 2010 Annual Research Report   Final Research Report ( PDF )
  • 2009 Annual Research Report
  • Research Products

    (22 results)

All 2010 2009

All Journal Article (13 results) (of which Peer Reviewed: 10 results) Presentation (9 results)

  • [Journal Article] Requirement of TCF7L2 for TGF-(3-idependent transcriptional activation of the TMEPAI gene.2010

    • Author(s)
      Nakano N, Itch S, Watanabe Y, Maeyama K, Itoh F, Kato M.
    • Journal Title

      J.Biol.Chem. 285

      Pages: 38023-38033

    • Related Report
      2010 Final Research Report
    • Peer Reviewed
  • [Journal Article] Flkl-GFP BAC Tg mice: an animal model for the study of blood vessel development.2010

    • Author(s)
      Ishitobi H, Matsumoto K, Azami T, Itoh F, Itoh S, Takahashi S, Ema M.
    • Journal Title

      Exp.Anim. 59

      Pages: 615-622

    • Related Report
      2010 Final Research Report
    • Peer Reviewed
  • [Journal Article] Inhibition of endothelial cell activation by bHLH protein E2-2 and its impairment of angiogenesis.2010

    • Author(s)
      Tanaka A, Itoh F, Nishiyama K, Takezawa T, Kurihara H, Itch S, Kato M.
    • Journal Title

      Blood 115

      Pages: 4138-4147

    • Related Report
      2010 Final Research Report
    • Peer Reviewed
  • [Journal Article] TMEPAI, a transmembrane TGF-(3-inducible protein, sequesters Smad proteins from active participation in TGF-(3 signaling.2010

    • Author(s)
      Watanabe Y, Itch S, Goto T, Ohnishi E, Inamitsu M, Itoh F, Satoh K, Wiercinska E, Yang W, Shi L, Tanaka A, Nakano N, Mommaas AM, Shibuya H, ten Duke P, Kato M.
    • Journal Title

      Mol.Cell 37

      Pages: 123-134

    • Related Report
      2010 Final Research Report
    • Peer Reviewed
  • [Journal Article] 血管新生におけるTGF-βファミリーの役割と疾患2010

    • Author(s)
      伊東史子、伊東進、加藤光保
    • Journal Title

      実験医学 28

      Pages: 877-882

    • Related Report
      2010 Final Research Report
  • [Journal Article] Requirement of TCF7L2 for TGF-β-idependent transcriptional activation of the TMEPAI gene.2010

    • Author(s)
      Nakano N
    • Journal Title

      J.Biol.Chem.

      Volume: 285 Pages: 649-662

    • Related Report
      2010 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Flkl-GEP BAC Tg mice : an animal model for the study of blood vessel development2010

    • Author(s)
      Ishitobi H
    • Journal Title

      Exp.Animals.

      Volume: 59 Pages: 615-622

    • Related Report
      2010 Annual Research Report
    • Peer Reviewed
  • [Journal Article] TGF-βファミリーによる血管新生制御機構2010

    • Author(s)
      伊東史子
    • Journal Title

      医学のあゆみ

      Volume: 23 Pages: 923-927

    • Related Report
      2010 Annual Research Report
  • [Journal Article] Inhibition of endothelial cell activation by bHLH protein E2-2 and its impairment of angiogenesis.2010

    • Author(s)
      Aya Tanaka
    • Journal Title

      Blood (In press)(印刷中)

    • Related Report
      2009 Annual Research Report
    • Peer Reviewed
  • [Journal Article] TMEPAI, a transmembrane TGF-β-inducible protein, sequesters Smad proteins from active participation in TGF-beta signaling.2010

    • Author(s)
      Watanabe Y.
    • Journal Title

      Mol.Cell 15

      Pages: 123-134

    • Related Report
      2009 Annual Research Report
    • Peer Reviewed
  • [Journal Article] 血管新生におけるTGF-βシグナルの役割と疾患2010

    • Author(s)
      伊東史子
    • Journal Title

      実験医学 28

      Pages: 877-882

    • Related Report
      2009 Annual Research Report
  • [Journal Article] Poor vessel formation in Embryos from Knock-in Mice Expressing ALK5 with L45 loop mutation defective in Smad activation.2009

    • Author(s)
      Itoh F, Itoh S, Carvalho R.L.C, Adachi T, Ema M, Goumans MJ, Larsson J, Takahashi S, Mummery CL, ten Duke P, Kato M.
    • Journal Title

      Lab.Invest. 89

      Pages: 800-810

    • Related Report
      2010 Final Research Report
    • Peer Reviewed
  • [Journal Article] TALL/SCL relieves the E2-2-mediated repression of VEGFR2 promoter activity.2009

    • Author(s)
      Tanaka A, Itoh F, Itch S, Kato M.
    • Journal Title

      J.Biochem. 145

      Pages: 129-35

    • Related Report
      2010 Final Research Report
    • Peer Reviewed
  • [Presentation] 血管・リンパ管の安定性維持におけるTGF-βシグナルの役割2010

    • Author(s)
      伊東史子
    • Organizer
      第18回血管生物医学会
    • Place of Presentation
      優秀ポスター賞受(大阪)賞
    • Year and Date
      2010-12-03
    • Related Report
      2010 Final Research Report
  • [Presentation] 血管・リンパ管の安定性維持におけるTGF-βシグナルの役割解明2010

    • Author(s)
      Itoh F.
    • Organizer
      第18回血管生物医学会
    • Place of Presentation
      梅田スカイビル大阪
    • Year and Date
      2010-12-03
    • Related Report
      2010 Annual Research Report
  • [Presentation] Vascular endothelial cell-specific Smad2 and Smad3 signaling is required for blood vessel integrity.2010

    • Author(s)
      Itoh F, Itch S, Adachi T, Kato M
    • Organizer
      The 59^<th> Fujiwara International Seminar.
    • Place of Presentation
      Tomakomai, Japan
    • Year and Date
      2010-07-15
    • Related Report
      2010 Final Research Report
  • [Presentation] Impairment of vascular stability by endothelial specific ablation for Smad2 and Smad3 genes2010

    • Author(s)
      Itoh F, Itch S, Adachi T, Festing M, Weinstein M, Kato M
    • Organizer
      the 16^<th> International Vascular Biology Meeting.
    • Place of Presentation
      Los Angeles, California, U.S.
    • Related Report
      2010 Final Research Report
  • [Presentation] Impairment of vascular stability by endothelial specific ablation for Smad2 and Smad3 genes.2009

    • Author(s)
      Itoh F, Itoh S, Kato M
    • Organizer
      第32回日本分子生物学会年会
    • Place of Presentation
      横浜(ワークショップ、シンポジスト)
    • Year and Date
      2009-12-11
    • Related Report
      2010 Final Research Report
  • [Presentation] Impairment of vascular stability by endothelial specific ablation for Smad2 and Smad3 genes2009

    • Author(s)
      Fumiko Itoh
    • Organizer
      第32回分子細胞生物学会
    • Place of Presentation
      パシフィコ横浜 神奈川県
    • Year and Date
      2009-12-11
    • Related Report
      2009 Annual Research Report
  • [Presentation] Impairment of vascular stability by endothelial specific ablation for Smad2 and Smad3 genes2009

    • Author(s)
      Fumiko Itoh
    • Organizer
      第32回日本血管生物医学会
    • Place of Presentation
      東京大学安田講堂 東京都
    • Year and Date
      2009-10-08
    • Related Report
      2009 Annual Research Report
  • [Presentation] bHLH型転写因子E2-2はVEGFR2の発現を阻害し血管新生を阻害する2009

    • Author(s)
      Fumiko Itoh
    • Organizer
      第68回日本癌学会学術総会
    • Place of Presentation
      パシフィコ横浜 神奈川県
    • Year and Date
      2009-10-02
    • Related Report
      2009 Annual Research Report
  • [Presentation] The TGF-β signaling : Impairment of vascular stability by endothelial specific ablation for Smad2 and Smad3 genes.2009

    • Author(s)
      伊東史子
    • Organizer
      FASEB Summer Research Conference. Carefree
    • Place of Presentation
      Arizona, U.S.(招待講演)
    • Related Report
      2010 Final Research Report

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Published: 2009-04-01   Modified: 2016-04-21  

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