Vessel maturation by a cytokine TGFbeta1 and crosstalk with VEGFR2 signaling

• Project/Area Number: 25461132
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Cardiovascular medicine
• Research Institution: Kagawa University
• Principal Investigator: Igarashi Junsuke 香川大学, 医学部, 准教授 (20346638)
• Co-Investigator(Kenkyū-buntansha): HASHIMOTO TAKESHI 香川大学, 医学部, 助教 (80380153) ; 小坂 博昭 香川大学, 医学部, 教授 (60158897)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2015: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2014: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2013: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000)
• Keywords: 血管新生 / 内皮細胞 / 受容体 / サイトカイン / 成長因子

Outline of Final Research Achievements

Angiogenesis is a process in which new blood vessels arise from pre-existing ones. A better understanding of angiogenesis may lead to a development of novel therapeutic interventions for a wide array of disease states.
In the present study, we focused on a maturation process of newly formed vessels, and revealed novel actions of a cytokine TGFbeta1. Furthermore, we have newly synthesized a pro-angiogenic adenosine-like agent termed COA-Cl. COA-Cl on the one hand induces VEGF to promote vessel sprouting from fibroblasts, and on the other hand stimulates S1P1 receptor in vascular endothelial cells to promote vessel maturation. Thus, these findings may contribute for the development of a pharmacological intervention to modulate angiogenic processes.

Research Products

• [Journal Article] Design, synthesis, and evaluation of novel 2-halogenated or aminated carbocyclic oxetanocin a analogs as potential angiogenic agents. (2016)
  • Author(s): Sakakibara N, Igarashi J, Takata M, Konishi R, Suzue N, Kato Y, Maruyama T, and Tsukamoto I.
  • Journal Title: Heterocycles Volume: 印刷中
  • NAID: 40020609194
  • Peer Reviewed
• [Journal Article] A key role of PGC-1α transcriptional coactivator in production of VEGF by a novel angiogenic agent COA-Cl in cultured human fibroblasts. (2016)
  • Author(s): Igarashi J, Okamoto R, Yamashita T, Hashimoto T, Karita S, Nakai K, Kubota Y, Takata M, Yamaguchi F, Tokuda M, Sakakibara N, Tsukamoto I, Konishi R, Hirano K.
  • Journal Title: Physiological Reports Volume: 4 Issue: 6 Pages: e12742-e12742
  • DOI: 10.14814/phy2.12742
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Synthesis and Evaluation of Novel Carbocyclic Oxetanocin A (COA-Cl) Derivatives as Potential Tube Formation Agents (2015)
  • Author(s): N. Sakakibara,* J. Igarashi, M. Takata, Y. Demizu, T. Misawa, M. Kurihara, R. Konishi, Y. Kato, T. Maruyama, I. Tsukamoto
  • Journal Title: Chemical and Pharmaceutical Bulletin Volume: 63 Issue: 9 Pages: 701-709
  • DOI: 10.1248/cpb.c15-00386
  • NAID: 130005096030
  • ISSN: 0009-2363, 1347-5223
  • Peer Reviewed
• [Journal Article] Eicosapentaenoic acid upregulates VEGF-A through both GPR120 and PPARγ mediated pathways in 3T3-L1 adipocytes. (2015)
  • Author(s): Hasan AU, Ohmori K, Konishi K, Igarashi J, Hashimoto T, Kamitori K, Yamaguchi
  • Journal Title: Mol Cell Endocrinol. Volume: 406 Pages: 10-18
  • DOI: 10.1016/j.mce.2015.02.012
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Involvement of S1P1 receptor pathway in angiogenic effects of a novel adenosine-like nucleic acid analog COA-Cl in cultured human vascular endothelial cells (2014)
  • Author(s): Igarashi J, Hashimoto T, Kubota Y, Shoji K, Maruyama T, Sakakibara N, TakuwaY, Ujihara Y, Katanosaka Y, Mohri S, Naruse K, Yamashita T, Okamoto R, Hirano K, Kosaka H, Takata M, Konishi R, Tsukamoto I.
  • Journal Title: Pharmacology Research & Perspectives Volume: 2 Issue: 5 Pages: 68-68
  • DOI: 10.1002/prp2.68
  • Peer Reviewed / Open Access
• [Presentation] COA-Cl（コアクロル）による血管新生促進作用に関わる細胞内情報伝達の仕組み (2016)
  • Author(s): 五十嵐淳介
  • Organizer: 第93回日本生理学会大会
  • Place of Presentation: 北海道札幌市
  • Year and Date: 2016-03-22
  • Invited
• [Presentation] A Key Role of PGC-1α Co-transcription Factor, but not HIF1α Transcription Factor, in Production of Vascular Endothelial Growth Factor (VEGF) by a Novel Angiogenic Agent COA-Cl in Cultured Human Fibroblasts. (2015)
  • Author(s): Okamoto R, Igarashi J, Yamashita T, Takeshi Hashimoto T, Karita S, Shoji K, Kubota Y, Takata M, Yamaguchi F, Tokuda M, Sakakibara N, Tsukamoto I, Konishi R, Hirano K.
  • Organizer: Scientific Sessions 2015, American Heart Association
  • Place of Presentation: アメリカ合衆国フロリダ州オーランド市
  • Year and Date: 2015-11-07
  • Int'l Joint Research
• [Presentation] Activation of cAMP/CREB/PGC-1α Pathway Plays a Key Role for a Novel Adenosine-like Angiogenic Agent COA-Cl to Induce Production of Vascular Endothelial Growth Gactor (VEGF) in Cultured Human Fibroblasts. (2015)
  • Author(s): Okamoto R, Igarashi J, Hashimoto T, Yamashita T, Shoji K, Kubota Y, Sakakibara N, Tsukamoto I, Konishi R, Hirano K.
  • Organizer: Scientific Sessions 2015, American Heart Association
  • Place of Presentation: アメリカ合衆国フロリダ州オーランド市
  • Year and Date: 2015-11-07
  • Int'l Joint Research
• [Presentation] 新規アデノシン類似化合物COA-Cl（コアクロル）はcAMP/CREB/PGC-1αの経路を介して血管内皮成長因子（VEGF）の産生を促進する (2015)
  • Author(s): 岡本隆司、五十嵐淳介、橋本剛、山下哲生、苅田咲子、窪田泰夫、高田麻紀、小西良士、塚本郁子、平野勝也
  • Organizer: 第67回日本生理学会中国四国地方会
  • Place of Presentation: 鳥取県米子市
  • Year and Date: 2015-10-24
• [Presentation] 苅田咲子、五十嵐淳介、岡本隆司、山下哲生、橋本剛、窪田泰夫、塚本郁子、小西良士、平野勝也 (2015)
  • Author(s): 新規アデノシン類似化合物COA-Cl（コアクロル）はヒト皮膚由来線維芽細胞において結合組織成長因子（CTGF）の発現を抑制する
  • Organizer: 第67回日本生理学会中国四国地方会
  • Place of Presentation: 鳥取県米子市
  • Year and Date: 2015-10-24
• [Presentation] A novel adenosine-like angiogenic agent COA-Cl elevates VEGF production via the transcription co-activator PGC-1α in cultured human fibroblasts. (2015)
  • Author(s): Igarashi J, Tsukamoto I, Hirano K.
  • Organizer: 第79回日本循環器学会学術集会
  • Place of Presentation: 大阪府大阪市
  • Year and Date: 2015-04-24
• [Presentation] A novel angiogenic agent COA-Cl induced PGC-1α-mediated VEGF production in cultured human fibroblasts. (2015)
  • Author(s): Okamoto R, Igarashi J, Yamashita T, Hashimoto T, Shoji K, Kubota Y, Takata M, Tsukamoto I, Konishi R, Hirano K
  • Organizer: 第92回日本生理学会総会
  • Place of Presentation: 兵庫県神戸市
  • Year and Date: 2015-03-22 – 2015-03-24
• [Presentation] 血管新生における内皮細胞の受容体シグナルの役割（教育講演） (2014)
  • Author(s): 五十嵐淳介
  • Organizer: 第66回日本皮膚科学会西部支部学術大会
  • Place of Presentation: 香川県高松市
  • Year and Date: 2014-11-08 – 2014-11-09
  • Invited
• [Presentation] アデノシン類似化合物COA-ClによるVEGF分泌促進機序の検討 (2014)
  • Author(s): 岡本隆司 五十嵐淳介 山下哲生 橋本剛 平野勝也 高田麻紀 小西良士 塚本郁子 小路和代 窪田泰夫
  • Organizer: 第66回日本生理学会中国四国地方会
  • Place of Presentation: 香川県高松市
  • Year and Date: 2014-11-01 – 2014-11-02
• [Presentation] 新規核酸類似物質COA-Clによる血管新生反応におけるS1P1受容体の役割 (2014)
  • Author(s): 五十嵐淳介、窪田泰夫、小路和代、榊原紀和、丸山徳見、高田真紀、小坂博昭、多久和陽、橋本剛、山下哲生、小西良二、塚本郁子
  • Organizer: 第91回日本生理学会大会
  • Place of Presentation: 鹿児島市
• [Presentation] S1P1 Receptors Mediate Angiogenic Responses Of A Novel Adenosine Analogue COA-Cl In Human Umbilical Vein Endothelial Cells (HUVEC) (2013)
  • Author(s): Junsuke Igarashi, Yasuo Kubota, Kazuyo Shoji, Norikazu Sakakibara, Tokumi Maruyama, Maki Takata, Hiroaki Kosaka, Ryoji Konishi, Ikuko Tsukamoto
  • Organizer: Scientific Sessions, American Heart Association
  • Place of Presentation: アメリカ合衆国テキサス州ダラス市