In vivo imaging of the spatiotemporal activity of the angiogenic signaling pathways

• Project Area: Mutli-dimensional fluorescence live imaging of cellular function and molecular activity
• Project/Area Number: 22113009
• Research Category: Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• 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): 2010-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥109,850,000 (Direct Cost: ¥84,500,000、Indirect Cost: ¥25,350,000); Fiscal Year 2014: ¥16,380,000 (Direct Cost: ¥12,600,000、Indirect Cost: ¥3,780,000); Fiscal Year 2013: ¥17,290,000 (Direct Cost: ¥13,300,000、Indirect Cost: ¥3,990,000); Fiscal Year 2012: ¥18,070,000 (Direct Cost: ¥13,900,000、Indirect Cost: ¥4,170,000); Fiscal Year 2011: ¥17,940,000 (Direct Cost: ¥13,800,000、Indirect Cost: ¥4,140,000); Fiscal Year 2010: ¥40,170,000 (Direct Cost: ¥30,900,000、Indirect Cost: ¥9,270,000)
• Keywords: 血管新生 / ゼブラフィッシュ / 蛍光イメージング / 細胞形態・運動 / 細胞増殖 / 血管内皮細胞 / 遺伝子発現 / 蛍光生体イメージング / シグナル伝達 / ｂカテニン / βカテニン / 尾側静脈 / バイオイメージング

Outline of Final Research Achievements

Blood vessel networks running throughout the body carry blood to supply oxygen and nutrients to all the cells in the body. In this study, we have investigated the molecular mechanism of vascular network formation by performing multidimensional fluorescence live-imaging analyses using zebrafish as a model animal. Here, we have clarified 1) the signaling pathways underlying endothelial cell morphology and motility during angiogenesis, 2) the role of transcriptional regulator -catenin in vascular development and 3) the regulatory mechanism of endothelial cell proliferation during vascular development.

Research Products

• [Journal Article] Tip cell specific requirement for an atypical Gpr124 and Reck-dependent Wnt/β-catenin pathway during brain angiogenesis. (2015)
  • Author(s): Vanhollebeke B., Stone O., Bostaille N., Cho C., Zhou Y., Maquet E., Gauquier A., Cabochette P., Fukuhara S., Mochizuki N., Nathans J. and Stainier D.Y.R.
  • Journal Title: eLife Volume: 未定
  • Peer Reviewed
• [Journal Article] Recent advances in understanding of cardiovascular development by imaging of zebrafish. (2015)
  • Author(s): Fukuhara S, Fukui H, Wakayama Y, Ando K, Nakajima H, Mochizuki N.
  • Journal Title: Dev Growth Differ. Volume: 未定 Issue: 4 Pages: 109-122
  • DOI: 10.1111/dgd.12210
  • Peer Reviewed / Open Access
• [Journal Article] RhoA and ROCK mediate histamine-induced vascular leakage and anaphylactic shock. (2015)
  • Author(s): Mikelis CM, Simaan M, Ando K, Fukuhara S, Sakurai A, Amornphimoltham P, Masedunskas A, Weigert R, Chavakis T, Adams RH, Offermanns S, Mochizuki N, Zheng Y, Gutkind JS.
  • Journal Title: Nat. Commun. Volume: 6 Issue: 1 Pages: 6725-6725
  • DOI: 10.1038/ncomms7725
  • Peer Reviewed
• [Journal Article] Cdc42 mediates Bmp-induced sprouting angiogenesis through Fmnl3-driven assembly of endothelial filopodia in zebrafish. (2015)
  • Author(s): Wakayama Y, Fukuhara S (Corresponding author), Ando K, Matsuda M, Mochizuki N.
  • Journal Title: Dev. Cell. Volume: 32 Issue: 1 Pages: 109-122
  • DOI: 10.1016/j.devcel.2014.11.024
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] β-Catenin-dependent transcription is central to Bmp-mediated formation of venous vessels. (2015)
  • Author(s): Kashiwada T, Fukuhara S (Co-corresponding author), Terai K, Tanaka T, Wakayama Y, Ando K, Nakajima H, Fukui H, Yuge S, Saito Y, Gemma A, Mochizuki N.
  • Journal Title: Development Volume: 142 Pages: 497-509
  • DOI: 10.1242/dev.115576
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] S1P-Yap1 signaling regulates endoderm formation required for cardiac precursor cell migration in zebrafish. (2014)
  • Author(s): Fukui H, Terai K, Nakajima H, Chiba A, Fukuhara S, Mochizuki N.
  • Journal Title: Dev. Cell. Volume: 31 Issue: 1 Pages: 128-136
  • DOI: 10.1016/j.devcel.2014.08.014
  • Peer Reviewed
• [Journal Article] Visualizing the cell-cycle progression of endothelial cells in zebrafish. (2014)
  • Author(s): Fukuhara S (Co-corresponding author), Zhang J, Yuge S, Ando K, Wakayama Y, Sakaue-Sawano A, Miyawaki A, Mochizuki N.
  • Journal Title: Dev. Biol. Volume: 393 Issue: 1 Pages: 10-23
  • DOI: 10.1016/j.ydbio.2014.06.015
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] The secreted protein ANGPTL2 promotes metastasis of osteosarcoma cells through integrin alpha5beta1, p38 MAPK, and matrix metalloproteinases. (2014)
  • Author(s): Odagiri et al.
  • Journal Title: Science Signaling Volume: 7 Issue: 309
  • DOI: 10.1126/scisignal.2004612
  • Peer Reviewed / Open Access
• [Journal Article] Coexpression of Ang1 and Tie2 in Odontoblasts of Mouse Developing and Mature Teeth—A New Insight into Dentinogenesis (2014)
  • Author(s): Nakajima et al.
  • Journal Title: ACTA HISTOCHEMICA ET CYTOCHEMICA Volume: 47 Issue: 1 Pages: 19-25
  • DOI: 10.1267/ahc.13043
  • NAID: 130003390846
  • ISSN: 0044-5991, 1347-5800
  • Peer Reviewed / Open Access
• [Journal Article] Rap1 regulates actin cytoskeleton at endothelial cell-cell junctions by spatially controlling myosin II activlty (2013)
  • Author(s): Ando K, S. Fukuhara, Y. Obars, T. Noriya. N. Nakahata, N. Moohizuki.
  • Journal Title: Journal of Cell Biology Volume: 202 Issue: 6 Pages: 901-916
  • DOI: 10.1083/jcb.201301115
  • Peer Reviewed
• [Journal Article] The parallel growth of motoneuron axons with the dorsal aorta depends on Vegfc/Vegfr3 signaling in zebrafish (2013)
  • Author(s): Kwon HB, Fukuhara S, Asakawa K, Ando K, Kashiwada T, Kawakami K Hibi M, Kwon YG, Kim KW, Alitalo K, Mochizuki N.
  • Journal Title: Development Volume: 140 Issue: 19 Pages: 4081-4090
  • DOI: 10.1242/dev.091702
  • Peer Reviewed
• [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] 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] 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] 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 quies cence 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 ・- 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] Unveiling the cellular and molecular mechanism of vascular development by fluorescence-based bio-imaging in zebrafish (2015)
  • Author(s): Shigetomo Fukuhara.
  • Organizer: The Joint Meeting of the 120th Annual Meeting of The Japanese Association of Anatomists and the 92nd Annual Meeting of The Physiological Society of Japan.
  • Place of Presentation: Kobe
  • Year and Date: 2015-03-21
  • Invited
• [Presentation] 血管新生メカニズムの蛍光生体イメージング解析 (2014)
  • Author(s): 福原茂朋
  • Organizer: 生理研研究会2014「心血管膜輸送分子の構造・機能・病態の統合的研究戦略」
  • Place of Presentation: 岡崎
  • Year and Date: 2014-09-04
• [Presentation] Visualization of -catenin transcriptional activity in endothelial cells uncovers a novel role for β-catenin in venous vessel development in zebrafish (2014)
  • Author(s): Shigetomo Fukuhara, Naoki Mochizuki.
  • Organizer: The 18th International Vascular Biology Meeting
  • Place of Presentation: Kyoto
  • Year and Date: 2014-04-15
• [Presentation] Visualization of beta-catenin transcriptional activity in endothelial cells uncovers a novel role for beta-catenin in venous vessel development in zebrafish (2014)
  • Author(s): Shigetomo Fukuhara, Naoki Mochizuki
  • Organizer: The 18th International Vascular Biology Meeting (IVBM2014)
  • Place of Presentation: 京都ミヤコメッセ
  • Invited
• [Presentation] 血管形成を制御するシグナル伝達系 (2014)
  • Author(s): 福原茂朋、望月直樹、
  • Organizer: 第87回日本薬理学会年会
  • Place of Presentation: 仙台
  • Invited
• [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
  • Year and Date: 2013-02-08
• [Presentation] 血管形成ダイナミクスの生体イメージング (2013)
  • Author(s): 福原茂朋、望月直樹
  • Organizer: 第36回日本分子生物学会
  • Place of Presentation: 神戸
  • Invited
• [Presentation] 蛍光イメージングによる血管形成メカニズムの解析 ～血管安定化・成熟化を制御する分子メカニズム～ (2013)
  • Author(s): 福原茂朋
  • Organizer: 第1回関西血管生物研究会2013（KVBM2013）
  • Place of Presentation: 大阪
• [Presentation] 蛍光イメージング技術を駆使した血管形成メカニズムの解析 (2013)
  • Author(s): 福原茂朋
  • Organizer: 生理研研究会2013「心血管膜輸送分子の構造・機能・病態の統合的研究戦略」
  • Place of Presentation: 岡崎
• [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明 (2013)
  • Author(s): 福原茂朋、望月直樹
  • Organizer: 第69回日本顕微鏡学会学術講演会
  • Place of Presentation: 大阪
  • Invited
• [Presentation] ゼブラフィッシュの蛍光イメージング解析による血管形成メカニズムの解明 (2013)
  • Author(s): 福原茂朋、望月直樹
  • Organizer: 第21回日本血管生物医学会
  • Place of Presentation: 大阪
  • Invited
• [Presentation] Fluorescence-based Bio-imaging of Vascular Development using Transgenic Zebrafish (2013)
  • Author(s): Shigetomo Fukuhara
  • Organizer: The 11th Korea-Japan Joint Symposium on Vascular Biology
  • Place of Presentation: Jeju, Korea
  • Invited
• [Presentation] Deciphering the molecular mechanism underlying developmental angiogenesis by fluorescence-based bio-imaging in zebrafish (2013)
  • Author(s): Shigetomo Fukuhara
  • Organizer: The Joint Symposium of 2nd Asia-Pacific Vascular Biology and 10th Frontiers of Biomedical Sciences.
  • Place of Presentation: Tainan, Taiwan
  • Invited
• [Presentation] In vivo imaging of signal transduction pathways involved in angiogenesis (2012)
  • Author(s): Shigetomo Fukuhara
  • Organizer: The 10th Korea-Japan Joint Symposium on Vascular
  • 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
  • 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
  • Place of Presentation: 岡山
  • Year and Date: 2012-09-12
• [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 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
  • 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: 北海道・北海道大学
  • Year and Date: 2011-06-27
• [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] 「ゼブラフィッシュを用いたin vivo細胞生物学研究 ～血管研究を例に～」、生体の科学 (2015)
  • Author(s): 福原茂朋、若山勇紀、柏田建、安藤康史、望月直樹
  • Publisher: 金沢一郎記念医学医療振興財団
• [Book] 「Cdc42はフォーミンタンパク質Fmnl3を介して内皮細胞におけるフィロポディアの形成を促進し血管新生を誘導する」、ライフサイエンス新着論文レビュー (2014)
  • Author(s): 若山勇紀、福原茂朋.
  • Publisher: DBCLS
• [Book] Signaling pathways regulating endothelial cell-cell junctions as a barrier to tumor metastasis. In “Tight junctions in cancer metastasis” (2013)
  • Author(s): Shigetomo Fukuhara, Naoki Mochizuki
  • Total Pages: 15
  • Publisher: Springer
• [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
  • Total Pages: 8
  • Publisher: 医薬ジャーナル社
• [Book] 「in vivoイメージング」、血管新生研究の最先端 (2013)
  • Author(s): 若山勇紀、福原茂朋
  • Total Pages: 10
  • Publisher: 医薬ジャーナル社
• [Book] 血管内皮細胞のシグナルと接着による血管成熟化・安定化機構、最新医学 (2013)
  • Author(s): 安藤康史ら
  • Total Pages: 6
  • Publisher: 最新医学社
• [Book] 血管内皮細胞に発現するスフィンゴシン 1-リン酸輸送体Spns2によるリンパ球の血管内移動の制御機構、生化学 (2013)
  • Author(s): 福原茂朋、望月直樹
  • Total Pages: 4
  • Publisher: 日本生化学会
• [Book] 神経-血管伴走性の成立機序―ゼブラフィッシュをモデルとした研究、血管医学 (2013)
  • Author(s): Hyouk-Bum Kwonら
  • Total Pages: 5
  • Publisher: メディカルビュー社
• [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」 (2013)
  • Author(s): 福原 茂朋
  • Total Pages: 8
  • 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] 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] 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] 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/index.html
• [Remarks]
  • URL: http://www.ncvc.go.jp/res/divisions/structural_analvsis/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