Physiological and pathophysiological role of sphingosine-1-phosphate signaling in vascular system

• Project/Area Number: 25293050
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: General physiology
• Research Institution: National Cardiovascular Center Research Institute
• Principal Investigator: FUKUHARA SHIGETOMO 国立研究開発法人国立循環器病研究センター, 研究所, 室長 (70332880)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥14,560,000 (Direct Cost: ¥11,200,000、Indirect Cost: ¥3,360,000); Fiscal Year 2015: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2014: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2013: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000)
• Keywords: スフィンゴシン－1－リン酸 / Spns2 / 血管 / リンパ管 / 発生 / 内皮細胞 / ホメオスタシス / 動脈硬化 / 血管バリア / 血管内皮細胞

Outline of Final Research Achievements

In this study, we have investigated physiological and pathophysiological role of bioactive lipid mediator sphingosine-1-phosphate (S1P), focusing on its transporter, Spns2. As a result, we found that S1P secreted from endothelial cells through Spns2 promotes endothelial cell-cell junctions in an autocrine manner, thereby maintaining the integrity of lymphatic vessels. In addition, we also investigated the physiological role of S1P in zebrafish development and found that S1P released from yolk syncytial layer through Spns2 induces activation of nuclear transcription factor Yap1 to regulate endoderm formation, which is required for migration of cardiac precursor cells. Therefore, S1P/S1P2/Yap1 signaling regulates cardiac development through endoderm formation.

Research Products

• [Journal Article] Clarification of mural cell coverage of vascular endothelial cells by live imaging of zebrafish. (2016)
  • Author(s): Ando K, Fukuhara S, Izumi N, Nakajima H, Fukui H, Kelsh RN, Mochizuki N.
  • Journal Title: Development Volume: 143 Pages: 1328-1339
  • DOI: 10.1242/dev.132654
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Protein kinase A (PKA) Type I interacts with P-Rex1, a Rac guanine nucleotide exchange factor: Effect on PKA localization and P-Rex1 signaling. (2016)
  • Author(s): Chávez-Vargas L., Adame-García S.R., Cervantes-Villagrana R.D., Castillo-Kauil A., Bruystens J.G.H., Fukuhara S., Taylor S.S., Mochizuki N., Reyes-Cruz G., Vázquez-Prado J.
  • Journal Title: J. Biol. Chem. Volume: 291 Issue: 12 Pages: 6182-6199
  • DOI: 10.1074/jbc.m115.712216
  • Peer Reviewed
• [Journal Article] Endothelial Ca 2+ oscillations reflect VEGFR signaling-regulated angiogenic capacity in vivo (2015)
  • Author(s): Yokota Y*, Nakajima H*(Co-first author), Wakayama Y, Muto A, Kawakami K, Fukuhara S, Mochizuki N.
  • Journal Title: eLife Volume: 4
  • DOI: 10.7554/elife.08817
  • Peer Reviewed / Open Access
• [Journal Article] PRMT8 as a phospholipase regulates Purkinje cell dendritic arborization and motor coordination. (2015)
  • Author(s): Kim, J.D., Park, K.E., Ishida, J., Kako, K., Hamada, J., Kani, S., Takeuchi, M., Namiki, K., Fukui, H., Fukuhara, S., Hibi, M,. Kobayashi, M., Kanaho, Y., Kasuya, Y., Mochizuki, N., Fukamizu, A.
  • Journal Title: Sci. Adv. Volume: 1 Issue: 11
  • DOI: 10.1126/sciadv.1500615
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Autonomy and non-autonomy of angiogenic cell movements revealed by experiment-driven mathematical modeling (2015)
  • Author(s): Sugihara K, Nishiyama K, Fukuhara S, Uemura A, Arima S, Kobayashi R, Kohn-Luque A, Mochizuki N, Suda T, Ogawa S, Kurihara H
  • Journal Title: Cell Rep Volume: 13 Issue: 9 Pages: 1814-1827
  • DOI: 10.1016/j.celrep.2015.10.051
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Arf6 regulates tumour angiogenesis and growth through HGF-induced endothelial β1 integrin recycling. (2015)
  • Author(s): Hongu T, Funakoshi Y, Fukuhara S, Suzuki T, Sakimoto S, Takakura N, Ema M, Takahashi S, Itoh S, Kato M, Hasegawa H, Mochizuki N, Kanaho Y.
  • Journal Title: Nat. Commun. Volume: 6 Issue: 1 Pages: 7925-7925
  • DOI: 10.1038/ncomms8925
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [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., Stainier D.Y.R.
  • Journal Title: eLife Volume: 4
  • DOI: 10.7554/elife.06489
  • Peer Reviewed
• [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] 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] Tip cell specific requirement for an atypical Gpr124 and Reck-dependent Wnt/β-catenin pathway during brain angiogenesis. (2015)
  • Author(s): １.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] 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
• [Presentation] 血管新生におけるメカノトランスダクション機構の役割 (2016)
  • Author(s): 福原茂朋、望月直樹
  • Organizer: 第55回日本生体医工学会大会
  • Place of Presentation: 富山
  • Year and Date: 2016-04-26
  • Invited
• [Presentation] Unveiling the cellular and molecular mechanism underlying vascular development by fluorescence-based bio-imaging in zebrafish (2015)
  • Author(s): Shigetomo Fukuhara.
  • Organizer: 10th World Congress for Microcirculation.
  • Place of Presentation: 京都
  • Year and Date: 2015-09-25
  • Int'l Joint Research / Invited
• [Presentation] Dynamic regulation of endothelial barrier function (2015)
  • Author(s): 福原茂朋、望月直樹
  • Organizer: 第21回日本遺伝子治療学会学術集会
  • Place of Presentation: 大阪
  • Year and Date: 2015-07-24
  • Invited
• [Presentation] In vivo細胞生物学研究による血管構築メカニズムの解析 (2015)
  • Author(s): 福原茂朋、望月直樹
  • Organizer: 第67回細胞生物学会大会
  • Place of Presentation: 東京
  • Year and Date: 2015-06-30
  • Invited
• [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] 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21回日本血管生物医学会
  • 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
• [Book] 『生体の科学』特集「細胞シグナル操作法」 (2015)
  • Author(s): 福原茂朋.
  • Total Pages: 2
  • Publisher: 金沢一郎記念医学医療振興財団
• [Book] 血管系におけるアンジオポエチン-Tie受容体システムの役割、Thrombosis Medicine (2015)
  • Author(s): 福原茂朋.
  • Total Pages: 7
  • Publisher: 先端医学社
• [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, 柏田健, 安藤康史, 望月直樹.
  • Total Pages: 7
  • Publisher: 金沢一郎記念医学医療振興財団
• [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: ライフサイエンス統合データベースセンター
• [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