The role of TGF-・・signaling in Angiogenesis

2010 Fiscal Year Final Research Report

• Project/Area Number: 21890022
• Research Category: Grant-in-Aid for Research Activity Start-up
• Allocation Type: Single-year Grants
• Research Field: Experimental pathology
• Research Institution: University 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
• Keywords: TGF-・ / 血管新生 / Smad2 / 3 / conditional knockout / リンパ管

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.

Research Products

• [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
  • 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
  • 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
  • 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
  • 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
• [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
  • 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
  • Peer Reviewed
• [Presentation] Impairment of vascular stability by endothelial specific ablation for Smad2 and Smad3 genes (2010)
  • 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.
  • Year and Date: 20100620-20100624
• [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
• [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
• [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)
  • Year and Date: 20090628-20090703
• [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