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The pathological investigation of proliferative diabetic retinopathy based on the control of retinal pericytes

Research Project

Project/Area Number 12470363
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Ophthalmology
Research InstitutionKYOTO UNIVERSITY

Principal Investigator

TAKAGI Hitoshi  Department of Ophthalmology and Visual Science, Kyoto University, Lecturer, 医学研究科, 講師 (70283596)

Co-Investigator(Kenkyū-buntansha) NISHIWAKI Hirokazu  Department of Ophthalmology and Visual Science, Kyoto University, Instructor, 医学研究科, 助手 (90303841)
KIRYU Junichi  Department of Ophthalmology and Visual Science, Kyoto University, Lecturer, 医学研究科, 講師 (80281096)
KASHII Satoshi  Department of Ophthalmology and Visual Science, Kyoto University, Associate Professor, 医学研究科, 助教授 (50194717)
SUZUMA Kiyoshi  Department of Ophthalmology and Visual Science, Kyoto University, Instructor, 医学研究科, 助手 (80335265)
万代 道子  京都大学, 医学研究科, 助手 (80263086)
Project Period (FY) 2000 – 2002
Project Status Completed (Fiscal Year 2002)
Budget Amount *help
¥14,100,000 (Direct Cost: ¥14,100,000)
Fiscal Year 2002: ¥3,800,000 (Direct Cost: ¥3,800,000)
Fiscal Year 2001: ¥3,900,000 (Direct Cost: ¥3,900,000)
Fiscal Year 2000: ¥6,400,000 (Direct Cost: ¥6,400,000)
Keywordsendothelial cells / pericytes / angiopoietin 2 / AT 1 receptor / angiotensin / diabetic retinopathy / retinal edema / PDGF-receptor / 内皮-周皮細胞間制御機構 / pericyte loss / アンジオテンシン / ATI阻害薬 / アンジオポエチン1 / ストレプトゾトシン糖尿病ラット / アンジオポイエチン1 / Tie2 / VEGFファミリー / アンジオポイエチン / アンジオランシン / VEGF / 血管増殖 / 透過性
Research Abstract

In this research, we investigated the control mechanism of retinal endothelial cells and pericytes, and aimed at a new therapeutic development of intraocular vascular proliferative diseases. In a diabetic retinopathy, pericyte loss is known to cause microaneuiysms and vascular hyperpermiability. In streptozotocine-induced diabetic rats, angiopoietine 2 is proved to be highly expressed after 6 months from onset of diabetes by RT-PCR analyses, and pericyte loss is observed by in situ hybridization and double immune staining analyses in the retinal cite where angiopoietine 2 is expressed. (IOVS 2003;44;393-402). In the eyes of diabetic retinopathy, angiotensin 2 selectively potentiates angiopoietine 2 in retinal endothelial cells, and this suggests the role of angiotensin 2 in the relation between endothelial cells and pericytes. (Diabetes 2001;50;867-875). These results are highly evaluated as a basic data on clinical trials, such as DIRECT study. In the next, we aimed a new therapeutic development on such vessels in which pericytes are degenerated. The injection of an antagonistic mAb against PDGFR-beta into murine neonates provides such pericyte loss of retinal vessels, and vessels of such mice are poorly remodeled and leaky. This model resembles a pathological change in diabetic retinopathy. We show that addition of recombinant modified angiopoietin 1 restored a hierarchical valculature, and also rescued retinal edema and hemorrhage in the complete absensce of pericytes. These observations demonstrate the potential of angiopoietin 1 as a new therapeutic modality for pericyte loss in diseases such as diabetic retinopathies. (JCI 2002;110;1619-28). Angiopoietin 1 and angiotensin type 1 receptor blocker are possible to be an effective drug in a diabetic retinopathy.

Report

(4 results)
  • 2002 Annual Research Report   Final Research Report Summary
  • 2001 Annual Research Report
  • 2000 Annual Research Report
  • Research Products

    (30 results)

All Other

All Publications (30 results)

  • [Publications] Otani A, et al.: "Angiotensin-II induces expression of the Tie2 receptor ligand, angiopoietin-2, in bovine retinal endothelial cells"Diabetes. 50. 867-875 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Oh H, et al.: "Selective induction of neuropilin-1 by vasculer endothelial growth factor (VEGF) : A novel mechanism contributing to VEGF-induced angiogenesis"Proc Natl Acad Sci USA. 99. 383-388 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Otani A, et al.: "Vascular Endothelial Growth Factor Family and Receptor Expression in Human Choroidal Neovascular Membrane"Microvasc Res. 64. 162-169 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Takagi H, et al.: "Role of Vitronectin Receptor-type Integrins and Osteopontin in Ischemia-Induced Retinal Neovascularization"Jpn J Ophthalnol. 46. 270-278 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Miyamoto N, et al.: "Contrasting Effect of Estrogen on VEGF Induction under Different Oxygen Status and Its Role in Murine. Retinopathy of Prematurity"Invest Ophthalmol Vis Sci. 43. 2007-2014 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Uemura A, et al.: "Recombinant angiopoietin-1 restores higher-order architecture of growing blood vessels in mice in the absence of mural cells"J Clin Invest. 110. 1619-1628 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Otani, A, et al.: "Angiotensin II induces expression of the Tie2 receptor ligand, angiopoietin-2, in bovine retinal endothelial cells"Diabetes. 50(4). 867-875 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Oh, H, et al.: "Selective induction of neuropilin-1 by vascular endothelial growth factor (VEGF): a mechanism contributing to VEGF-induced angiogenesis"Proc Natl Acad Sci U S A. 99(1). 383-388 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Otani, A, et al.: "Vascular endothelial growth factor family and receptor expression in human choroidal neovascular membranes"Microvasc Res. 64(1). 162-169 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Takagi, H, et al.: "Role of vitronectin receptor-type integrins and osteopontin in ischemia-induced retinal neovascularization"Jpn J Ophthalmol. 46(3). 270-278 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Miyamoto, N, et al.: "Contrasting effect of estrogen on VEGF induction under different oxygen status and its role in murine ROP"Invest Ophthalmol Vis Sci. 43(6). 2007-2014 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Uemurra, A, et al.: "Recombinant angiopoietin-1 restores higher-order architecture of growing blood vessels in mice in the absence of mural cells"J Clin Invest. 110(11). 1619-1628 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Otani A: "Angiotensin-II Induces Expression of the Tie2 Receptor Ligand, Angiopoietin-2, in Bovine Retinal Endothelial Cells"Diabetes. 50. 867-875 (2001)

    • Related Report
      2002 Annual Research Report
  • [Publications] Oh H: "Selective induction of neuropilin-1 by vascular endothelial growth factor (VEGF) : A mechanism contributing to VEGF-induced angiogenesis"Proc. Natl. Acad. Sci. USA. 99. 383-388 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Otaani A: "Vascular endothelial growth factor family and receptor expression in human choroidal neovascular membranes"Microvasc Res. 64. 162-169 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Takagi H: "Role of vitronectin receptor-type integrins and osteopontin in ischemia-induced retinal neovascularization"Jpn J Ophthalmol. 46. 270-278 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Miyamoto N: "Contrasting Effect of Estrogen on VEGF Induction under Different Oxygen Status and Its Role in Murine Retinopathy of Prematunity"Invest Ophthalmol Vis Sci. 43. 2007-2014 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Uemura A: "Recombinant angiopoietin-1 restores higher-order architecture of growing blood vessels in mice in the absence of mural cells"J Clin Invest. 110. 1619-1628 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Otani A, Takagi H, Oh H, Koyama S, Honda Y: "Angiotensin-II induces expression of the Tie2 receptor ligand, angiopoietin-2, in bovine retinal endothelial cells"Diabetes. 50. 867-875 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Otani A, Takagi H, Oh H, Koyama S, Ogura Y, Matsumura M, Honda Y: "Vascular Endothelial Growth Factor Family and Receptor Expression in Human Choroidal Neovascular Membranes"Microvascular Res.. (in press).

    • Related Report
      2001 Annual Research Report
  • [Publications] Takagi H, Suzuma K, Otani A, Oh H, Koyama S, Ohashi H, Honda Y: "Role of Vitronectin Receptor-Type Integrins and Osteopontin in Ischemia-Induced Retinal Neovascularization"Jpn.J.Ophthalmol. (in press).

    • Related Report
      2001 Annual Research Report
  • [Publications] Miyamoto M, Mandai M, Takagi H, Suzuma I, Suzuma S, Honda Y: "Contrasting Effect of Estrogen on VEGF Induction under Different Oxygen Status and Its Role in Murine Retinopathy of Prematuity"Invest Ophthalmol Vis.Sci.. (in press).

    • Related Report
      2001 Annual Research Report
  • [Publications] 大谷篤史: "Angiotensin II induces expression of the Tie2 Receptor ligand, angiopoietin-2 in bovine retinal endotherial cells"Diabetes. (印刷中).

    • Related Report
      2000 Annual Research Report
  • [Publications] 大谷篤史: "Angiotensin II-stimulated vascular endothelial growth factor expression in bovine retinal pericytes."Invest Ophthalmol Vis Sci. 41. 1192-1199 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] 野中淳元: "PKC-beta inhibitor (LY333531) attenuates leukocyte entrapment in retinal microcirculation of diabetic rats."Invest Ophthalmol Vis Sci. 41. 2702-2706 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] 王英泰: "Hypoxia and vascular endothelial growth factor selectively up-regulate angiopoietin-2 in bovine microvascular endothelial cells."J Biol Chem. 28. 15732-15739 (1999)

    • Related Report
      2000 Annual Research Report
  • [Publications] 鈴間潔: "Increased expression of KDR/Flk-1 (VEGFR-2) in murine model of ischemia-induced retinal neovascularization"Microvasc.Res. 56. 183-191 (1998)

    • Related Report
      2000 Annual Research Report
  • [Publications] 大谷篤史: "Angiotensin II potentiates vascular endothelial growth factor-induced angiogenic activity in retinal microcapillary endothelial cells."Cire Res. 23. 619-628 (1998)

    • Related Report
      2000 Annual Research Report
  • [Publications] 高木均: "血管新生病とVEGF.アンシオポイエチン"特集:Vasalar Biology-最近の進歩-The Lipid. 7 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] 高木均: "虚血後の血管新生はどのようにして起こるのか"細胞工学特集「虚血分子メカニズムと新しい治療法」. 6 (2000)

    • Related Report
      2000 Annual Research Report

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Published: 2000-04-01   Modified: 2016-04-21  

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