Vascular stabilization and destabilization by angiopoietin-1/Tie2 system

• Project/Area Number: 22390040
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: General physiology
• Research Institution: National Cardiovascular Center Research Institute
• Principal Investigator: FUKUHARA Shigetomo 独立行政法人国立循環器病研究センター, 研究所, 室長 (70332880)
• Project Period (FY): 2010 – 2012
• Project Status: Completed (Fiscal Year 2012)
• Budget Amount: ¥14,820,000 (Direct Cost: ¥11,400,000、Indirect Cost: ¥3,420,000); Fiscal Year 2012: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2011: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2010: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000)
• Keywords: アンジオポエチン / Tie2 / 血管新生 / 血管安定化 / Tie-2 / アンンジオポエチン

Research Abstract

In this study, we investigated the mechanism how Angiopoietin-1 (Ang1)-Tie2 signal promotes vascular stabilization. Here, we show that Ang1-Tie2 signal potentiates Notch signal through β-catenin-dependent up-regulation of Delta-like 4 expression, leading to basement membrane formation required for vascular stabilization. In addition, we report that Ang1-Tie2 signal induces reorganization of actin cytoskeleton through Rap1 small GTPase, thereby enhancing endothelial barrier function.

Research Products

• [Journal Article] PDZ-RhoGEF and LARG are essential for embryo development, and provide a link between thrombin and LPA receptors and Rho activation. (2013)
  • Author(s): Mikelis et al.
  • Journal Title: J. Biol. Chem. Volume: 288 Issue: 17 Pages: 12232-12243
  • DOI: 10.1074/jbc.m112.428599
  • Peer Reviewed
• [Journal Article] The sphingosine-1-phosphate transporter Spns2 expressed on endothelial cells regulates lymphocyte trafficking in mice (2012)
  • Author(s): Fukuhara S, et al
  • Journal Title: J Clin Invest Volume: (In press)(未定) Issue: 4 Pages: 1416-1426
  • DOI: 10.1172/jci60746
  • Peer Reviewed
• [Journal Article] Arhgef15 promotes retinal angiogenesis by mediating VEGF-induced Cdc42 activation and potentiating RhoJ inactivation in endothelial cells. (2012)
  • Author(s): Kusuhara S., Fukushima Y., Fukuhara S., Jakt L.M., Okada M., Shimizu Y., Hata M., Nishida K., Negi A., Hirashima M., Mochizuki N., Nishikawa S. and Uemura A.
  • Journal Title: PLoS One Volume: 7 Issue: 9 Pages: e45858-e45858
  • DOI: 10.1371/journal.pone.0045858
  • Peer Reviewed
• [Journal Article] Cardiac connexins, mutations and arrhythmias (2012)
  • Author(s): Delmar M, Makita N
  • Journal Title: Curr Opin Cardiol Volume: (in press) Issue: 1 Pages: 163-172
  • DOI: 10.1161/circep.111.967604
  • Peer Reviewed
• [Journal Article] Cytochalasin D enhances the accumulation of a protease-resistant form of prion protein in ScN2a Cells: Involvement of PI3 kinase/Akt signaling pathway. (2012)
  • Author(s): Takenouchi T. et al.
  • Journal Title: Cell Biol. Int. Volume: 36 Issue: 12 Pages: 1223-1231
  • DOI: 10.1042/cbi20120329
  • Peer Reviewed
• [Journal Article] A critical role for tumor cell-derived angiopoientin-like protein 2 in metastasis (2012)
  • Author(s): Endo M, et al
  • Journal Title: Cancer Research Volume: (in press) Issue: 7 Pages: 1784-1794
  • DOI: 10.1158/0008-5472.can-11-3878
  • Peer Reviewed
• [Journal Article] EphrinA/EphA signal facilitates insulin-like growth factor-I-induced myogenic differentiation through suppression of the Ras/extracellular signal-regulated kinase 1/2 cascade in myoblast cell lines (2011)
  • Author(s): Minami M., et al
  • Journal Title: Molecular Biology of the Cell Volume: 22 Issue: 18 Pages: 3508-3519
  • DOI: 10.1091/mbc.e11-03-0183
  • Peer Reviewed
• [Journal Article] Angiopoietin-1/Tie2 signal augments basal Notch signal controlling Vascular quiescence by inducing delta-like 4 expression through AKT-mediated activation of β-catenin (2011)
  • Author(s): Zhang J., et al
  • Journal Title: Journal of Biological Chemistry Volume: 286 Issue: 10 Pages: 8055-8066
  • DOI: 10.1074/jbc.m110.192641
  • Peer Reviewed
• [Journal Article] Angiopoietin-1/Tie2 signal augments basal Notch signal controlling vascular quiescence by inducing delta-like 4 expression through AKT-mediated activation of・-catenin. (2011)
  • Author(s): Zhang J.
  • Journal Title: J.Biol.Chem. Volume: 286 Pages: 8055-8066
  • Peer Reviewed
• [Journal Article] Vascular endothelial-cadherin stabilizes at cell-cell junctions by anchoring to circumferential actin bundles through α- and β-catenins in cyclic AMP-Epac-Rap1 signal-activated endothelial cells. (2010)
  • Author(s): Noda K., Zhang J., Fukuhara S., Kunimoto S., Yoshimura M. and Mochizuki N.
  • Journal Title: Mol. Biol. Cell Volume: 21 Issue: 4 Pages: 584-596
  • DOI: 10.1091/mbc.e09-07-0580
  • Peer Reviewed
• [Journal Article] Angiopoietin-1/Tie2 receptor signaling in vascular quiescence and angiogenesis. (2010)
  • Author(s): Fukuhara S., Sako K., Noda K., Zhang J., Minami M. and Mochizuki N.
  • Journal Title: Histol. Histopathol. Volume: 25 Pages: 384-396
  • URL: http://www.ncbi.nlm.nih.gov/pubmed/20054809
  • Peer Reviewed
• [Journal Article] Vascular endothelial-cadherin stabilizes at cell-cell junctions by anchoring to circumferential actin bundles through・- and・-catenins in cyclic AMP-Epac-Rap1 signal-activated endothelial cells. (2010)
  • Author(s): Noda K.
  • Journal Title: Mol.Biol.Cell Volume: 21 Pages: 584-596
  • Peer Reviewed
• [Journal Article] Angiopoietin-1/Tie2 receptor signaling in vascular quiescence and angiogenesis. (2010)
  • Author(s): Fukuhara S.
  • Journal Title: Histol.Histopathol. Volume: 25 Pages: 387-396
  • Peer Reviewed
• [Journal Article] Establishment of mice expressing EGFP in the placode-derived inner ear sensory cell lineage and FACS-array analysis focused on the regional specificity of the otocyst. (2010)
  • Author(s): Fujimoto C.
  • Journal Title: J.Comp.Neurol. Volume: 518 Pages: 4702-4722
  • Peer Reviewed
• [Presentation] スフィンゴシン-1-リン酸を介した血管内皮細胞による免疫系の制御 (2013)
  • Author(s): 福原茂朋
  • Organizer: 第42回日本心脈管作動物質学会、シンポジウム2「心血管病研究の最前線」
  • Place of Presentation: 奈良
  • Year and Date: 2013-02-09
• [Presentation] スフィンゴシン-１-リン酸を介した血管内皮細胞による免疫系の制御 (2013)
  • Author(s): 福原茂朋
  • Organizer: 第42回日本心脈管作動物質学会
  • Place of Presentation: 奈良
• [Presentation] In vivo imaging of signal transduction pathways involved in angiogenesis (2012)
  • Author(s): Shigetomo Fukuhara, Naoki Mochizuki
  • Organizer: The 10th Korea-Japan Joint Symposium on Vascular Biology & The 20th Annual Meeting of the Japanese Vascular Biology and Medicine Organization. Symposium.
  • Place of Presentation: Tokushima, Japan
  • Year and Date: 2012-12-05
• [Presentation] スフィンゴシン-1-リン酸トランスポーターSpns2の生理的機能 (2012)
  • Author(s): 福原茂朋
  • Organizer: 生理研研究会「細胞センサーの分子機構・相互関連・ネットワーク研究会」
  • Place of Presentation: 岡崎
  • Year and Date: 2012-11-30
• [Presentation] イメージングによる血管新生メカニズムの解析 (2012)
  • Author(s): 福原茂朋
  • Organizer: 日本動物学会第83回大会、シンポジウム「神経系・血管系の新生と再生に関する最近の進展と展望」
  • Place of Presentation: 大阪
  • Year and Date: 2012-09-13
• [Presentation] 蛍光生体イメージングによる血管新生メカニズムの解析 (2012)
  • Author(s): 福原茂朋
  • Organizer: 第22回日本数理生物学会、シンポジウム
  • Place of Presentation: 岡山
  • Year and Date: 2012-09-12
• [Presentation] In vivo imaging of signal transduction pathways involved in angiogenesis (2012)
  • Author(s): Shigetomo Fukuhara
  • Organizer: 第42回日本心脈管作動物質学会
  • Place of Presentation: 徳島
• [Presentation] スフィンゴシン-１-リン酸トランスポーターSpns2の生理的機能 (2012)
  • Author(s): 福原茂朋
  • Organizer: 生理研研究会「細胞センサーの分子機構・相互関連・ネットワーク研究会」
  • Place of Presentation: 岡崎
• [Presentation] イメージングによる血管新生メカニズムの解析 (2012)
  • Author(s): 福原茂朋
  • Organizer: 日本動物学会第83回大会
  • Place of Presentation: 大阪
• [Presentation] 蛍光生体イメージングによる血管新生メカニズムの解析 (2012)
  • Author(s): 福原茂朋
  • Organizer: 第22回日本数理生物学会
  • Place of Presentation: 岡山
• [Presentation] Visualization of endothelial cell cycle progression during vascular network formation (2011)
  • Author(s): 福原茂朋
  • Organizer: 第19回日本血管生物医学会
  • Place of Presentation: 東京・東京ステーションコンファレンス
  • Year and Date: 2011-12-09
• [Presentation] Visualization of endothelial cell dynamics during vascular network formation by in vivo bioimaging (2011)
  • Author(s): Shigetomo Fukuhara
  • Organizer: Cell Signaling Network 2011. Symposium
  • Place of Presentation: Merida, Mexico
  • Year and Date: 2011-10-26
• [Presentation] Visualization of endothelial cell cycle progression during vascular network formation (2011)
  • Author(s): Shigetomo Fukuhara
  • Organizer: The Satellite Meeting in Osaka for the 2^<nd> Pacific Symposium on Vascular Biology
  • Place of Presentation: 大阪・大阪大学
  • Year and Date: 2011-10-26
• [Presentation] Visualization of endothelial cell dynamics during vascular network formation by in vivo bioimaging (2011)
  • Author(s): Shigetomo Fukuhara
  • Organizer: Cell Signaling Network 2011
  • Place of Presentation: Yucatan, Merida, Mexico
  • Year and Date: 2011-10-26
• [Presentation] 生体蛍光イメージングによる血管ネットワーク形成機構の解析 (2011)
  • Author(s): 福原茂朋、望月直樹
  • Organizer: 第84回日本生化学、シンポジウム
  • Place of Presentation: 京都
  • Year and Date: 2011-09-24
• [Presentation] 生体蛍光イメージングによる血管ネットワーク形成機構の解析 (2011)
  • Author(s): 福原茂朋
  • Organizer: 第84回日本生化学
  • Place of Presentation: 京都・国立京都国際会館
  • Year and Date: 2011-09-24
• [Presentation] 蛍光イメージングを用いたin vivo細胞生物学による血管形成機構の解析 (2011)
  • Author(s): 福原茂朋
  • Organizer: 第63回日本細胞生物学会
  • Place of Presentation: 札幌・北海道大学
  • Year and Date: 2011-06-27
• [Presentation] Signaling pathways regulating endothelial barrier functions (2010)
  • Author(s): Shigetomo Fukuhara, Koji Ando, Kazuomi Noda, Jianghui Zhang, Naoki Mochizuki
  • Organizer: The 8th Korea-Japan Joint Symposium on Vascular Biology & The 18th Annual Meeting of the Japanese Vascular Biology and Medicine Organization. Symposium.
  • Place of Presentation: Osaka, Japan
  • Year and Date: 2010-12-03
• [Presentation] Signaling pathways regulating endothelial barrier functions (2010)
  • Author(s): Fukuhara S.
  • Organizer: The 8th Korea-Japan Joint Symposium on Vascular Biology & The 18th Annual Meeting of the Japanese Vascular Biology and Medicine Organization. (Symposium)
  • Place of Presentation: 大阪
  • Year and Date: 2010-12-03
• [Presentation] Visualization of endothelial cell cycle progression in vivo (2010)
  • Author(s): Fukuhara S.
  • Organizer: 武田国際シンポジウム「Casting Light on Life」
  • Place of Presentation: 東京
  • Year and Date: 2010-12-01
• [Book] 「血管新生に関わる細胞内シグナル伝達」、血管新生研究の最先端 (2013)
  • Author(s): 福原 茂朋
  • Publisher: 医薬ジャーナル社
• [Book] 血管新生研究の最先端、「in vivoイメージング」 (2013)
  • Author(s): 若山 勇紀、福原 茂朋
  • Total Pages: 10
  • Publisher: 医薬ジャーナル社
• [Book] Signaling pathways regulating endothelial cell-cell junctions as a barrier to tumor metastasis. In “Tight junctions in cancer metastasis” (2013)
  • Author(s): Fukuhara S. et al.
  • Total Pages: 15
  • Publisher: Springer
• [Book] (2012)
  • Publisher: メディカルビュー社
• [Book] 「蛍光生物学」の最前線8-1「ゼブラフィッシュの蛍光イメージングによる血管形成メカニズムの解析」 (2012)
  • Author(s): 福原 茂朋、若山 勇紀
  • Publisher: DOJIN News
• [Book] 血管新生研究の最先端、「血管新生に関わる細胞内シグナル伝達」 (2012)
  • Author(s): 福原 茂朋
  • Total Pages: 8
  • Publisher: 医薬ジャーナル社
• [Book] 再生医療、学会印象記「第19回日本血管生物医学会学術集会」 (2012)
  • Author(s): 福原 茂朋
  • Total Pages: 2
  • Publisher: メディカルビュー社
• [Book] 「細胞小器官と細胞骨格」「PECAM-1」「カドヘリン」、血管生物学辞典 (2011)
  • Author(s): 福原 茂朋
  • Publisher: 朝倉書店
• [Book] 血管医学,生きた細胞・生物を用いた血管構築を理解するためのイメージング (2011)
  • Author(s): 福原茂朋
  • Total Pages: 8
  • Publisher: メディカルビュー社
• [Book] 血管内皮細胞間接着を制御するシグナル伝達機構、薬学雑誌 (2010)
  • Author(s): 福原 茂朋、望月 直樹
  • Publisher: 日本薬学会
• [Book] アンジオポエチン-1 による血管安定化メカニズム、日本薬理学雑誌くすりとからだ (2010)
  • Author(s): 福原 茂朋、望月 直樹
  • Publisher: 日本薬理学会
• [Book] 血管内皮細胞間接着による血管安定化・成熟化、実験医学(増刊 : 血管研究と血管治療) (2010)
  • Author(s): 福原 茂朋、張 江暉、野田 一臣、望月 直樹
  • Publisher: 羊土社
• [Book] 血管新生・恒常性の維持、生化学 (2010)
  • Author(s): 福原 茂朋、望月 直樹
  • Publisher: 日本生化学会
• [Book] Ang1-Tie2による血管透過性制御、Annual Review循環器 (2010)
  • Author(s): 福原 茂朋、望月 直樹
  • Publisher: 中外医学社
• [Book] Annunal Review循環器2010(Ang1-Tie2による血管透過性制御) (2010)
  • Author(s): 福原茂朋
  • Total Pages: 7
  • Publisher: 中外医学社
• [Book] 血管内皮細胞間接着を制御するシグナル伝達機構 (2010)
  • Author(s): 福原茂朋
  • Total Pages: 8
  • Publisher: 薬学雑誌
• [Book] 血管内皮細胞間接着による血管安定化・成熟化、実験医学(増刊:血管研究と血管治療) (2010)
  • Author(s): 福原茂朋
  • Total Pages: 7
  • Publisher: 羊土社
• [Book] アンジオポエチン-1による血管安定化メカニズム (2010)
  • Author(s): 福原茂朋
  • Total Pages: 5
  • Publisher: 日本薬理学雑誌くすりとからだ
• [Book] 血管新生・恒常性の維持 (2010)
  • Author(s): 福原茂朋
  • Total Pages: 12
  • Publisher: 生化学
• [Remarks]
  • URL: http://www.ncvc.go.jp/res/divisions/structural_analysis/index.html
• [Remarks]
  • URL: http://plaza.umin.ac.jp/~ncvc/
• [Remarks]
  • URL: http://www.ncvc.go.jp/res/divisions/structural_analysis/index.html
• [Remarks]
  • URL: http://plaza.umin.ac.jp/ncvc/index.html
• [Remarks]
  • URL: http://www.ncvc.go.jp/res/divisions/structural_analysis/index.html