Analysis of the molecular and cellular mechanism of vessel maturation in adult tissues

• Project/Area Number: 19K07116
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 47040:Pharmacology-related
• Research Institution: Shinshu University
• Principal Investigator: Numaga-Tomita Takuro 信州大学, 学術研究院医学系, 准教授 (60705060)
• Project Period (FY): 2019-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2021: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 血管成熟 / 血管平滑筋 / TRPC6チャネル / 血流回復 / 内皮障害 / TRPC6 / 交感神経 / 電位依存性L型カルシウムチャネル / 冠血管 / 神経成長因子 / L型カルシウムチャネル / 血管新生 / 細胞内カルシウム伝達 / 血管形成 / がん / 創傷治癒 / 壁細胞

Outline of Research at the Start

生体の恒常性維持には機能的な血管網の存在が欠かせない。血管は発達に従って備わるものであるが、成熟個体においても組織障害時に血管網は再形成され、組織の修復・恒常性の回復に貢献する。機能的な血管網の形成には、構造的に脆い微小血管が、より構造的に安定な血管へと成熟していく過程“血管成熟”が重要である。しかしながら、血管成熟は様々な要素が複雑に絡みあった組織応答であり、いまだその制御機構の全容は明らかにされていない。本研究申請は、この血管成熟の機構を解明することで、血管形成不全を伴う多くの疾患に対して有効な治療方法を開発する基盤を目指す。

Outline of Final Research Achievements

The functional blood vessels play critical roles in body homeostasis. While blood vessels were developmentally formed, once adult tissue have injured, newly formed vascular network contributes to recovery of tissue homeostasis. Formation of functional vascular network requires vessel maturation in which vulnerable nascent capillaries are covered and stabilized by mural cells. Since vessel maturation was complex process involving many factors, the comprehensive molecular and cellular mechanism is still unknown. In this study, we demonstrated that TRPC6 expressed in vascular smooth muscle cells functions as a negative regulator of vessel maturation and the pharmacological suppression of TRPC6 facilitates it even with the endothelial dysfunction. Therefore, TRPC6 could be a druggable target for the ischemic diseases.

Academic Significance and Societal Importance of the Research Achievements

本研究では、血管平滑筋に発現するTRPC6チャネルが成体における血管成熟の負の制御因子であることを明らかにした。TRPC6を抑制した血管平滑筋細胞およびマウス個体の解析から、TRPC6の抑制が、どのような分子・細胞機構により血管成熟を促進させうるかが明らかになった。本研究における特に重要な発見が、TRPC6の抑制により、血管平滑筋の分化を促進すると内皮障害のレベルも軽減されることである。すなわち、血管平滑筋の表現型の正常化こそが血管の恒常性維持に重要であることが示された。TRPC6は明らかにそこに関与する重要な分子の一つであり、虚血性疾患の予後改善などに有効な創薬標的であることを明らかにした。

Research Products

• [Int'l Joint Research] NIEHS/NIH(米国)
• [Int'l Joint Research] Catholic University of Argentina(アルゼンチン)
• [Int'l Joint Research] Dongguk University-Seoul(韓国)
• [Int'l Joint Research] Mahidol University(タイ)
• [Int'l Joint Research] University Malaysia Sabah(マレーシア)
• [Journal Article] Inhibition of transient receptor potential cation channel?6 promotes capillary arterialization during post‐ischaemic blood flow recovery (2022)
  • Author(s): Numaga‐Tomita Takuro、Shimauchi Tsukasa、Kato Yuri、Nishiyama Kazuhiro、Nishimura Akiyuki、Sakata Kosuke、Inada Hiroyuki、Kita Satomi、Iwamoto Takahiro、Nabekura Junichi、Birnbaumer Lutz、Mori Yasuo、Nishida Motohiro
  • Journal Title: British Journal of Pharmacology Volume: 180 Issue: 1 Pages: 94-110
  • DOI: 10.1111/bph.15942
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] A TRPC3/6 Channel Inhibitor Promotes Arteriogenesis after Hind-Limb Ischemia. (2022)
  • Author(s): Shimauchi T, Numaga-Tomita T, Kato Y, Morimoto H, Sakata K, Matsukane R, Nishimura A, Nishiyama K, Shibuta A, Horiuchi Y, Kurose H, Kim SG, Urano Y, Ohshima T, Nishida M.
  • Journal Title: Cells Volume: 11 Issue: 13 Pages: 2041-2041
  • DOI: 10.3390/cells11132041
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] NRSF- GNAO1 Pathway Contributes to the Regulation of Cardiac Ca 2+ Homeostasis (2022)
  • Author(s): Inazumi Hideaki、Kuwahara Koichiro、Nakagawa Yasuaki、et al.
  • Journal Title: Circulation Research Volume: 130 Issue: 2 Pages: 234-248
  • DOI: 10.1161/circresaha.121.318898
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Gravity sensing in plant and animal cells. (2021)
  • Author(s): Takahashi K, Takahashi H, Furuichi T, Toyota M, Furutani-Seiki M, Kobayashi T, Watanabe-Takano H, Shinohara M, Numaga-Tomita T, Sakaue-Sawano A, Miyawaki A, Naruse K.
  • Journal Title: NPJ Microgravity Volume: 7 Issue: 1 Pages: 2-2
  • DOI: 10.1038/s41526-020-00130-8
  • Peer Reviewed / Open Access
• [Journal Article] beta-Arrestin-Biased AT1 Agonist, TRV027 Causes a Neonatal-Specific Sustained Positive Inotropic Effect without Increasing Heart Rate (2020)
  • Author(s): Kashihara T, Kawagishi H, Nakada T, Numaga-Tomita T, Kadota S, Wolf EE, Du CK, Shiba Y, Morimoto S, Yamada M.
  • Journal Title: Journal of the American College of Cardiology Volume: 5 Issue: 11 Pages: 1057-1057
  • DOI: 10.1016/j.jacbts.2020.08.011
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] TRPC Channels in Cardiac Plasticity (2020)
  • Author(s): Numaga-Tomita Takuro、Nishida Motohiro
  • Journal Title: Cells Volume: 9 Issue: 2 Pages: 454-454
  • DOI: 10.3390/cells9020454
  • Peer Reviewed / Open Access
• [Journal Article] TRPC3-Nox2 axis mediates nutritional deficiency-induced cardiomyocyte atrophy (2019)
  • Author(s): Sudi Suhaini Binti、Tanaka Tomohiro、Oda Sayaka、Nishiyama Kazuhiro、Nishimura Akiyuki、Sunggip Caroline、Mangmool Supachoke、Numaga-Tomita Takuro、Nishida Motohiro
  • Journal Title: Scientific Reports Volume: 9 Issue: 1 Pages: 9785-9785
  • DOI: 10.1038/s41598-019-46252-2
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] TRPC6 regulates phenotypic switching of vascular smooth muscle cells through plasma membrane potential‐dependent coupling with PTEN (2019)
  • Author(s): Numaga‐Tomita Takuro、Shimauchi Tsukasa、Oda Sayaka、Tanaka Tomohiro、Nishiyama Kazuhiro、Nishimura Akiyuki、Birnbaumer Lutz、Mori Yasuo、Nishida Motohiro
  • Journal Title: The FASEB Journal Volume: 33 Issue: 9 Pages: 9785-9796
  • DOI: 10.1096/fj.201802811r
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] 出産後心臓発達における交感神経支配の重要性の解明 (2022)
  • Author(s): 冨田 拓郎、川岸 裕幸、中田 勉、山田 充彦
  • Organizer: 第95回日本薬理学会年会
• [Presentation] 交感神経除神経が新生児心臓発達に与える影響の解析 (2021)
  • Author(s): 冨田 拓郎、川岸 裕幸、中田 勉、山田 充彦
  • Organizer: 第144回薬理学会関東部会
• [Presentation] 交感神経除神経が新生児・乳児の心臓発達に与える影響の解析 (2021)
  • Author(s): 冨田 拓郎, 川岸 裕幸, 中田 勉, 山田 充彦
  • Organizer: 第31回日本循環薬理学会
• [Presentation] The effect of chemical sympathetic innervation on the postnatal heart development. (2021)
  • Author(s): 冨田 拓郎、川岸 裕幸、中田 勉、山田 充彦
  • Organizer: 日本薬理学会
• [Presentation] 血管平滑筋細胞におけるL型電位依存性カルシウムチャネルとストア作動性カルシウムチャネルの関係性解明 (2020)
  • Author(s): 冨田 拓郎、小林 誠、川岸 裕幸、中田 勉、山田 充彦
  • Organizer: 日本循環薬理学会
• [Presentation] Analysis of the molecular mechanism underlying ER Ca2+ sensor STIM1-dependent suppression of CaV1.2 (2020)
  • Author(s): Takuro Numaga-Tomita, Hiroki Takahashi, Mitsuhiko Yamada
  • Organizer: 第97回日本生理学会大会
• [Presentation] 小胞体CaセンサーSTIM1によるCav1.2チャネル制御機構の解明 (2019)
  • Author(s): 冨田拓郎、高橋弘毅、山田充彦
  • Organizer: 第66回中部日本生理学会
• [Presentation] 血管平滑筋の表現型スイッチにおけるTRPC6チャネルの重要性の解明 (2019)
  • Author(s): 冨田拓郎、西田基宏
  • Organizer: 第29回日本循環薬理学会
• [Presentation] Importance of TRPC3-Nox2 coupling in cardiac stiffness (2019)
  • Author(s): Numaga-Tomita T, Shimauchi T, Kitajima N, Nishimura A, Nishida M
  • Organizer: 8th International Workshop Cardiac Mechano-Electric Coupling and Arrhythmias
  • Int'l Joint Research / Invited