• Search Research Projects
  • Search Researchers
  • How to Use
  1. Back to previous page

Molecular mechanism of cooperation between endothelial cell stiffness and functions.

Research Project

Project/Area Number 19K08583
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 53020:Cardiology-related
Research InstitutionShimane University

Principal Investigator

Okamoto Takayuki  島根大学, 学術研究院医学・看護学系, 准教授 (30378286)

Project Period (FY) 2019-04-01 – 2022-03-31
Project Status Completed (Fiscal Year 2021)
Budget Amount *help
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2021: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Keywords血管内皮細胞 / 細胞硬化 / 炎症 / 細胞骨格 / ギャップ結合 / 細胞接着 / メカノバイオロジー / 血管障害性疾患 / YAP
Outline of Research at the Start

我々は炎症時に血管内皮細胞が硬くなることを明らかにしてきた。本研究では、この細胞の硬化が、細胞の機能制御にどのように関わるかを解析する。ここでは細胞の硬さと機能を制御する可能性がある転写共役分子YAPに着目し、YAPの阻害または活性化が細胞の硬さ、細胞骨格の編成、細胞間相互作用に及ぼす影響を解析し、同時に血管内皮細胞機能の障害(炎症、血液凝固の病的活性化)がどのようにして連動して誘導されるのかを解明する。さらに動脈硬化症および血栓症モデルマウスを用いてYAPの活性化と病変部の形成および硬さ変化を解析する。一連の研究によって、血管硬化を基盤にした血管病変の形成機構を明らかにする。

Outline of Final Research Achievements

In the current study, we analyzed the mechanisms by which endothelial cells increased cell stiffness upon inflammatory stimuli to regulate cellular functions. We found that cytoskeletal reorganization and activation of the transcriptional coactivator YAP, are implicated in cell stiffening upon inflammatory stimuli, lead to suppress Notch1 signaling. Our data also revealed that the expression of pro-inflammatory and angiogenesis related genes in endothelial cells is regulated under Notch1 signaling pathway. Furthermore, we showed that recombinant thrombomodulin protein, an anticoagulant and anti-inflammatory factor, attenuates leukocyte adhesion by inducing cell softening. In summary, our results indicate intracellular signaling and cellular functional changes associated with endothelial cell stiffening and suggest that this molecular pathway may be useful for the control of vascular inflammation.

Academic Significance and Societal Importance of the Research Achievements

動脈血管の弾性増加(硬化)は、心血管イベント発症のリスクであり、また敗血症の予後不良に繋がる可能性が指摘されている。これは血管硬化が血栓形成や炎症の活性化を助長することを示唆し、我々は血管内皮細胞の硬化が炎症の増悪化を招く可能性を示してきた。本研究では細胞硬化を基軸として炎症拡大を引き起こす新しい分子機構を明らかにした点で学術的価値に優れる。また、本分子機構が動脈硬化や敗血症の基盤に存在する血管炎症を制御するための標的となる可能性を示し、これら疾患の新しい治療法への応用に繋がると考える。

Report

(4 results)
  • 2021 Annual Research Report   Final Research Report ( PDF )
  • 2020 Research-status Report
  • 2019 Research-status Report
  • Research Products

    (39 results)

All 2022 2021 2020 2019 Other

All Journal Article (19 results) (of which Int'l Joint Research: 2 results,  Peer Reviewed: 16 results,  Open Access: 13 results) Presentation (19 results) (of which Invited: 3 results) Remarks (1 results)

  • [Journal Article] GPR64, Screened from Ewing Sarcoma Cells, Is a Potential Target for Antibody-Based Therapy for Various Sarcomas2022

    • Author(s)
      Nakamura Koichi、Asanuma Kunihiro、Okamoto Takayuki、Yoshida Keisuke、Matsuyama Yumi、Kita Kouji、Hagi Tomohito、Nakamura Tomoki、Sudo Akihiro
    • Journal Title

      Cancers

      Volume: 14 Issue: 3 Pages: 814-814

    • DOI

      10.3390/cancers14030814

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Cytoskeletal Actin Structure in Osteosarcoma Cells Determines Metastatic Phenotype via Regulating Cell Stiffness, Migration, and Transmigration2021

    • Author(s)
      Kita Kouji、Asanuma Kunihiro、Okamoto Takayuki、Kawamoto Eiji、Nakamura Koichi、Hagi Tomohito、Nakamura Tomoki、Shimaoka Motomu、Sudo Akihiro
    • Journal Title

      Current Issues in Molecular Biology

      Volume: 43 Issue: 3 Pages: 1255-1266

    • DOI

      10.3390/cimb43030089

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Substrate stiffness modulates endothelial cell function via the YAP-Dll4-Notch1 pathway2021

    • Author(s)
      Matsuo Eri、Okamoto Takayuki、Ito Atsushi、Kawamoto Eiji、Asanuma Kunihiro、Wada Koichiro、Shimaoka Motomu、Takao Motoshi、Shimamoto Akira
    • Journal Title

      Experimental Cell Research

      Volume: 408 Issue: 1 Pages: 112835-112835

    • DOI

      10.1016/j.yexcr.2021.112835

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Endothelial connexin-integrin crosstalk in vascular inflammation2021

    • Author(s)
      Okamoto Takayuki、Park Eun Jeong、Kawamoto Eiji、Usuda Haruki、Wada Koichiro、Taguchi Akihiko、Shimaoka Motomu
    • Journal Title

      Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease

      Volume: 1867 Issue: 9 Pages: 166168-166168

    • DOI

      10.1016/j.bbadis.2021.166168

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Endotoxins and Non-Alcoholic Fatty Liver Disease2021

    • Author(s)
      Kessoku T, Kobayashi T, Imajo K, Tanaka K, Yamamoto A, Takahashi K, Kasai Y, Ozaki A, Iwaki M, Nogami A, Honda Y, Ogawa Y, Kato S, Higurashi T, Hosono K, Yoneda M, Okamoto T, Usuda H, Wada K, Kobayashi N, Saito S, Nakajima A
    • Journal Title

      Frontiers in Endocrinology

      Volume: 12 Pages: 770986-770986

    • DOI

      10.3389/fendo.2021.770986

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Leaky Gut: Effect of Dietary Fiber and Fats on Microbiome and Intestinal Barrier2021

    • Author(s)
      Usuda Haruki、Okamoto Takayuki、Wada Koichiro
    • Journal Title

      International Journal of Molecular Sciences

      Volume: 22 Issue: 14 Pages: 7613-7613

    • DOI

      10.3390/ijms22147613

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] The Lectin-Like Domain of Thrombomodulin Inhibits β1 Integrin-Dependent Binding of Human Breast Cancer-Derived Cell Lines to Fibronectin.2021

    • Author(s)
      Kawamoto E, Nago N, Okamoto T, Gaowa A, Masui-Ito A, Akama Y, Darkwah S, Appiah MG, Myint PK, Obeng G, Ito A, Caidengbate S, Esumi R, Yamaguchi T, Park EJ, Imai H, Shimaoka M.
    • Journal Title

      Biomedicines

      Volume: 9 Issue: 2 Pages: 162-162

    • DOI

      10.3390/biomedicines9020162

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Differential Expression of Pro-inflammatory and Pro-coagulant Genes in Endothelial Cells Induced by Porphyromonas gingivalis Lipopolysaccharide, Escherichia coli Lipopolysaccharide, and Zymosan.2020

    • Author(s)
      Hossain KH, Okamoto T, Usuda H, Israt JAHAN, Niibayashi T, Wada K.
    • Journal Title

      Shimane Journal of Medical Science

      Volume: 37 Pages: 123-132

    • NAID

      120007002118

    • Related Report
      2020 Research-status Report
    • Peer Reviewed
  • [Journal Article] Prognostic Significance of Thrombomodulin mRNA in High‐Grade Soft Tissue Sarcomas after 10?years2020

    • Author(s)
      Asanuma Kunihiro、Nakamura Tomoki、Asanuma Yumiko、Okamoto Takayuki、Kakimoto Takuya、Yada Yuki、Hagi Tomohito、Kita Kouji、Nakamura Koichi、Matsumine Akihiko、Sudo Akihiro
    • Journal Title

      Orthopaedic Surgery

      Volume: 12 Issue: 6 Pages: 1726-1732

    • DOI

      10.1111/os.12779

    • Related Report
      2020 Research-status Report
    • Peer Reviewed
  • [Journal Article] Recombinant Human Soluble Thrombomodulin Suppresses Monocyte Adhesion by Reducing Lipopolysaccharide-Induced Endothelial Cellular Stiffening2020

    • Author(s)
      Okamoto Takayuki、Kawamoto Eiji、Usuda Haruki、Tanaka Tetsuya、Nikai Tetsuro、Asanuma Kunihiro、Suzuki Koji、Shimaoka Motomu、Wada Koichiro
    • Journal Title

      Cells

      Volume: 9 Issue: 8 Pages: 1811-1811

    • DOI

      10.3390/cells9081811

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Soluble programmed death-ligand 1 rather than PD-L1 on tumor cells effectively predicts metastasis and prognosis in soft tissue sarcomas2020

    • Author(s)
      Asanuma Kunihiro、Nakamura Tomoki、Hayashi Akinobu、Okamoto Takayuki、Iino Takahiro、Asanuma Yumiko、Hagi Tomohito、Kita Kouji、Nakamura Kouichi、Sudo Akihiro
    • Journal Title

      Scientific Reports

      Volume: 10 Issue: 1 Pages: 1-9

    • DOI

      10.1038/s41598-020-65895-0

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Simulator-based pharmacological practice using iPad-Cloud system for medical education2020

    • Author(s)
      Wada Koichiro、Usuda Haruki、Tanaka Tetsuya、Okamoto Takayuki
    • Journal Title

      Folia Pharmacologica Japonica

      Volume: 155 Issue: 3 Pages: 185-186

    • DOI

      10.1254/fpj.19115

    • NAID

      130007839010

    • ISSN
      0015-5691, 1347-8397
    • Related Report
      2020 Research-status Report
    • Peer Reviewed
  • [Journal Article] Up-Regulated MicroRNA-27b Promotes Adipocyte Differentiation via Induction of Acyl-CoA Thioesterase 2 Expression2019

    • Author(s)
      Murata Yuka、Yamashiro Takashi、Kessoku Takaomi、Jahan Israt、Usuda Haruki、Tanaka Tetsuya、Okamoto Takayuki、Nakajima Atsushi、Wada Koichiro
    • Journal Title

      BioMed Research International

      Volume: 2019 Pages: 1-9

    • DOI

      10.1155/2019/2916243

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Rhamnan sulfate extracted from Monostroma nitidum attenuates blood coagulation and inflammation of vascular endothelial cells2019

    • Author(s)
      Okamoto Takayuki、Akita Nobuyuki、Terasawa Masahiro、Hayashi Tatsuya、Suzuki Koji
    • Journal Title

      Journal of Natural Medicines

      Volume: 印刷中 Issue: 3 Pages: 614-619

    • DOI

      10.1007/s11418-019-01289-5

    • NAID

      40021912735

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Anti-adhesive effects of human soluble thrombomodulin and its domains2019

    • Author(s)
      Kawamoto Eiji、Nago Nodoka、Okamoto Takayuki、Gaowa Arong、Masui-Ito Asami、Sakakura Yosuke、Akama Yuichi、Soe Zay Yar、Prajuabjinda Onmanee、Darkwah Samuel、Appiah Michael G.、Myint Phyoe Kyawe、Obeng Gideon、Park Eun Jeong、Imai Hiroshi、Shimaoka Motomu
    • Journal Title

      Biochemical and Biophysical Research Communications

      Volume: 511 Issue: 2 Pages: 312-317

    • DOI

      10.1016/j.bbrc.2019.02.041

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Molecular Mechanism of Matrine from Sophora alopecuroides in the Reversing Effect of Multi-Anticancer Drug Resistance in K562/ADR Cells2019

    • Author(s)
      Chen Zhi、Nishimura Nobuhiro、Okamoto Takayuki、Wada Koichiro、Naora Kohji
    • Journal Title

      BioMed Research International

      Volume: 2019 Pages: 1-10

    • DOI

      10.1155/2019/1269532

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] The role of vascular tissue stiffness and endothelial cellular stiffness2019

    • Author(s)
      OKAMOTO Takayuki
    • Journal Title

      Japanese Journal of Thrombosis and Hemostasis

      Volume: 30 Issue: 3 Pages: 496-504

    • DOI

      10.2491/jjsth.30.496

    • NAID

      130007663067

    • ISSN
      0915-7441, 1880-8808
    • Related Report
      2019 Research-status Report
  • [Journal Article] ギャップ結合を介した細胞間相互作用による血管内皮細胞の硬さと機能の制御2019

    • Author(s)
      岡本 貴行
    • Journal Title

      月刊「細胞」

      Volume: 51 Pages: 678-681

    • NAID

      40022118830

    • Related Report
      2019 Research-status Report
  • [Journal Article] ギャップ結合を介した細胞間相互作用による血管内皮細胞の硬さと機能の制御2019

    • Author(s)
      岡本 貴行
    • Journal Title

      アグリバイオ

      Volume: 13 Pages: 1283-1287

    • NAID

      40022118830

    • Related Report
      2019 Research-status Report
  • [Presentation] 細胞外環境の硬さによる血管内皮細胞の機能変化の解析2022

    • Author(s)
      岡本 貴行、臼田 春樹、和田 孝一郎
    • Organizer
      第95回日本薬理学会年会
    • Related Report
      2021 Annual Research Report
  • [Presentation] 口腔内細菌の保菌と好酸球性食道炎の関連性についての検討2022

    • Author(s)
      臼田 春樹、新林 友美、岡本 貴行、和田 孝一郎
    • Organizer
      第95回日本薬理学会年会
    • Related Report
      2021 Annual Research Report
  • [Presentation] miR-199a-3p と miR-126-3p は HIF-1α を標的として脂肪細分化を促進する2022

    • Author(s)
      Jahan Israt、岡本 貴行、臼田 春樹、田中 徹也、中島 淳、和田 孝一郎
    • Organizer
      第95回日本薬理学会年会
    • Related Report
      2021 Annual Research Report
  • [Presentation] 消化管粘膜透過性と多臓器連関: 創薬の対象としてのLeaky Gut Syndrome2022

    • Author(s)
      和田 孝一郎、臼田 春樹、岡本 貴行、新林 友美
    • Organizer
      第95回日本薬理学会年会
    • Related Report
      2021 Annual Research Report
    • Invited
  • [Presentation] 血管の硬化がもたらす血管内皮細胞の炎症性変化2021

    • Author(s)
      岡本 貴行
    • Organizer
      第49回日本救急医学会総会・学術集会
    • Related Report
      2021 Annual Research Report
    • Invited
  • [Presentation] 細胞接着基質の硬さがVEGF誘導性の血管内皮細胞の遺伝子発現に及ぼす影響2021

    • Author(s)
      岡本 貴行, 松尾 映里, 伊藤 温志, 川本 英嗣, 臼田 春樹, 和田 孝一郎, 島岡 要, 高尾 仁二, 島本 亮
    • Organizer
      第43回日本血栓止血学会 学術集会
    • Related Report
      2021 Annual Research Report
  • [Presentation] 口腔内細菌の保菌と好酸球性食道炎の関連性についての基礎的検討2021

    • Author(s)
      臼田 春樹、新林 友美、岡本 貴行、和田 孝一郎
    • Organizer
      第5回黒潮カンファレンス
    • Related Report
      2021 Annual Research Report
  • [Presentation] 細胞外環境の硬さが誘導する血管内皮細胞の遺伝子発現の解析2021

    • Author(s)
      岡本 貴行、臼田 春樹、和田 孝一郎
    • Organizer
      第5回黒潮カンファレンス
    • Related Report
      2021 Annual Research Report
  • [Presentation] リコモジュリンによる血管内皮細胞の硬化抑制とその役割2021

    • Author(s)
      岡本貴行、臼田春樹、田中徹也、和田孝一郎
    • Organizer
      第94回日本薬理学会年会
    • Related Report
      2020 Research-status Report
  • [Presentation] 食物繊維の欠乏が炎症性腸疾患に及ぼす影響に関する基礎的検討2021

    • Author(s)
      臼田 春樹、神田 翔磨、岡本 貴行、和田 孝一郎
    • Organizer
      第94回日本薬理学会年会
    • Related Report
      2020 Research-status Report
  • [Presentation] 細胞外環境の硬さによる血管内皮細胞の機能変化の解析2020

    • Author(s)
      岡本貴行, 松尾映里, 伊藤温志, 川本英嗣, 臼田春樹, 田中徹也, 和田孝一郎, 島岡要, 高尾仁二, 島本亮
    • Organizer
      第42回(2020年度)血栓止血学会
    • Related Report
      2020 Research-status Report
  • [Presentation] 細胞外環境の硬さがマクロファージの炎症性分化に及ぼす影響の解析2020

    • Author(s)
      岡本 貴行、臼田 春樹、田中 徹也、和田 孝一郎
    • Organizer
      第93回日本薬理学会年会
    • Related Report
      2019 Research-status Report
  • [Presentation] リコモジュリンが血管内皮細胞の硬さに及ぼす影響の解析2019

    • Author(s)
      岡本 貴行、川本 英嗣、臼田 春樹、田中 徹也、本田 剛一、和田 孝一郎、島岡 要
    • Organizer
      第34回(2019年度)日本Shock学会
    • Related Report
      2019 Research-status Report
  • [Presentation] 細胞外環境の硬さとマクロファージの炎症性分化2019

    • Author(s)
      岡本貴行、臼田春樹、田中徹也、和田孝一郎
    • Organizer
      第27回日本血管生物医学会学術集会
    • Related Report
      2019 Research-status Report
  • [Presentation] 血管内皮細胞の硬さ制御におけるYAPの役割2019

    • Author(s)
      岡本 貴行,臼田 春樹,田中 徹也, 川本 英嗣,島岡 要,和田孝一郎
    • Organizer
      第41回(2019年度)血栓止血学会要旨
    • Related Report
      2019 Research-status Report
  • [Presentation] 軟らかい細胞外環境はマクロファージの炎症性分化を抑制する2019

    • Author(s)
      岡本 貴行、臼田 春樹、田中 徹也、和田 孝一郎
    • Organizer
      第4回黒潮カンファレンス
    • Related Report
      2019 Research-status Report
  • [Presentation] 炎症性血管病変形成における血管内皮細胞の硬さ変化とその役割2019

    • Author(s)
      岡本 貴行
    • Organizer
      第1回三重血栓止血研究会
    • Related Report
      2019 Research-status Report
    • Invited
  • [Presentation] 細胞外環境の硬さとマクロファージの炎症性分化2019

    • Author(s)
      岡本 貴行、臼田 春樹、田中 徹也、和田 孝一郎
    • Organizer
      第72回日本薬理学会西南部会
    • Related Report
      2019 Research-status Report
  • [Presentation] 細胞外環境の硬さ依存的なマクロファージの分化傾向の解析2019

    • Author(s)
      岡本 貴行、臼田 春樹、田中 徹也、和田 孝一郎
    • Organizer
      第40回臨床薬理学会学術総会
    • Related Report
      2019 Research-status Report
  • [Remarks] 島根大学医学部薬理学講座

    • URL

      https://www.med.shimane-u.ac.jp/pharmacology/

    • Related Report
      2021 Annual Research Report 2020 Research-status Report 2019 Research-status Report

URL: 

Published: 2019-04-18   Modified: 2023-01-30  

Information User Guide FAQ News Terms of Use Attribution of KAKENHI

Powered by NII kakenhi