The role of TGF-・・signaling in Angiogenesis

TGF-·信号传导在血管生成中的作用

• 批准号: 21890022
• 负责人: ITOH Fumiko
• 金额: $ 1.7万
• 依托单位: University of Tsukuba
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Research Activity Start-up
• 财政年份: 2009
• 资助国家: 日本
• 起止时间: 2009 至 2010
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-21890022/
• 关键词: TGF-・; 血管新生; Smad2; 3; conditional knockout; リンパ管; TGF-β; Smad2/3; LYVE-1; N-cadherin

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.

为了阐明TGF-β/ALK 5/Smad 2/3信号通路调控血管发育的分子机制，我们从Smad 2/3条件灭活的小鼠建立了小鼠胚胎内皮细胞（MEECs）。我们检测了Smad 2/3 KO MEEC对切应力的反应，发现其对切应力无反应，并通过mRNA和miRNA芯片分析了其分子机制，发现Smad 2/3 KO MEEC中某些钙粘蛋白的表达较野生型MEEC降低。为了阐明TGF-β通路控制淋巴管发育的分子机制，我们采用Prox 1-Cre-ER转基因小鼠，条件性灭活LEC中的TGF-β II型受体（TβRII）。当我们在E10.5和E11.5时给予他莫昔芬（TM）时，TβRIIF/F ; Prox 1-CreER胚胎在E14.5时显示水肿。因此，我们分别用抗PECAM-1和抗LYVE-1抗体染色血管和淋巴管。有趣的是，血管似乎是建立良好的，而淋巴管只是存在，虽然他们是粗糙和组织不良。这些数据表明，TGF-β信号传导对于维持淋巴管完整性是不可或缺的。

项目成果

Flkl-GFP BAC Tg mice: an animal model for the study of blood vesseldevelopment.

Flkl-GFP BAC Tg 小鼠：用于研究血管发育的动物模型。

• 发表时间: 2010
• 期刊: Exp Anim.
• 作者: Ishitobi H;et al.
• 通讯作者: et al.

Poor vessel formation in embryos from knock-in mice expressing ALK5 with L45 loop mutation defective in Smad activation

• DOI: 10.1038/labinvest.2009.37
• 发表时间: 2009-07-01
• 期刊: LABORATORY INVESTIGATION
• 影响因子: 5
• 作者: Itoh, Fumiko;Itoh, Susumu;Kato, Mitsuyasu
• 通讯作者: Kato, Mitsuyasu

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

阐明TGF-β信号在维持血管和淋巴管稳定性中的作用

• 发表时间: 2010
• 作者: Tokoyoda;K.;Itoh F.
• 通讯作者: Itoh F.

TMEPAI, a transmembrane TGF-β-inducible protein, sequesters Smad proteins from active participation in TGF-beta signaling.

TMEPAI 是一种跨膜 TGF-β 诱导蛋白，可隔离 Smad 蛋白，使其不参与 TGF-β 信号传导。

• 发表时间: 2010
• 期刊: Mol.Cell 15
• 作者: Nakamura A.;et al.;Watanabe Y.
• 通讯作者: Watanabe Y.

血管新生におけるTGF-βシグナルの役割と疾患

TGF-β信号在血管生成和疾病中的作用

• 发表时间: 2010
• 期刊: 実験医学 28
• 作者: Nakamura A.;et al.;Watanabe Y.;伊東史子
• 通讯作者: 伊東史子