Regulation of vascular functions by bi-directional signaling between endothelial cells and pericytes

• Project/Area Number: 26670107
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• 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): 2014-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000); Fiscal Year 2015: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2014: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: ペリサイト / 血管内皮細胞 / シグナル / 壁細胞 / 血管機能 / 内皮細胞

Outline of Final Research Achievements

In this study, we investigated the mechanism by which mural cells (MCs) such as pericytes and vascular smooth muscle cells develop and cover endothelial cells (ECs) to regulate vascular stability and homeostasis by generating transgenic zebrafish lines that allow live imaging of MCs and by lineage tracing in vivo. MCs developed around the preformed arterial EC tubes possibly by arterial EC-derived signal. Subsequently, these nascent MCs actively proliferated and migrated along the EC tubes to cover entire vessels in response to platelet-derived growth factor signaling. The MCs covering the cranial vessels were derived from either neural crest cells or mesoderm, while those covering the vessels in the trunk were derived from mesoderm. Thus, live imaging and lineage tracing successfully enabled us to clarify precisely how MCs cover the EC tubes and to identify the origins of MCs.

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. (Co-corresponding author), Izumi N., Nakajima H., Fukui H., Kelsh R.N., Mochizuki N.
  • Journal Title: Development Volume: 143 Pages: 1328-1339
  • Peer Reviewed / 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): anhollebeke 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
• [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): 4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 (IVBM2014)
  • Place of Presentation: Kyoto
  • Year and Date: 2014-04-15
• [Book] 『生体の科学』特集「細胞シグナル操作法」 (2015)
  • Author(s): 福原茂朋
  • 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
  • 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.
  • 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