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Investigation of the role of Eph/Ephrin signaling in vasculogenesis and angiogenesis

Research Project

Project/Area Number 12835011
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research InstitutionKumamoto University

Principal Investigator

OIKE Yuichi  Kumamoto University, Institute of Molecular Embryology and Genetics, Department of Cell Differentiation, Assistant of Professor, 発生医学研究センター, 助手 (90312321)

Co-Investigator(Kenkyū-buntansha) SUDA Toshio  Kumamoto University, Institute of Molecular Embryology and Genetics, Department of Cell Differentiation, Professor, 発生医学研究センター, 教授 (60118453)
Project Period (FY) 2000 – 2001
Project Status Completed (Fiscal Year 2001)
Budget Amount *help
¥3,700,000 (Direct Cost: ¥3,700,000)
Fiscal Year 2001: ¥1,400,000 (Direct Cost: ¥1,400,000)
Fiscal Year 2000: ¥2,300,000 (Direct Cost: ¥2,300,000)
KeywordsVasculogenesis / Angiogenesis / Eph / Ephrin Signaling / 血管生物学 / 再生医学 / 分子生物学 / 受容体型チロシンキナーゼ
Research Abstract

Although the cellular and molecular mechanisms governing angiogenesis are only beginning to be understood, signaling through endothelial-restricted receptors, particularly receptor tyrosine kinases, have been shown to play a pivotal role in these events. Recent reports show that EphB receptor tyrosine kinases and their transmembrane-type ephrin-B2 ligands play essential roles in the embryonic vasculature. Eph receptor tyrosine kinases and their cell-surface-bound ligands, the ephrins mediate cell migration and adhesion. They contribute to developmental vascular assembly and body patterning, including directing axon guidance and building in the developing brain. These suggest that cell-to-cell repellent effects due to bi directional EphB/ephrin-B2 signaling may be crucial for vascular development similar to the mechanism described for neuronal development. To test this hypothesis, we disrupted the precise expression pattern of EphB/ephrin-B2 in vivo by generating transgenic (CAGp-ephrin … More -B2 Tg) mice that express ephrin-B2 under the control of a ubiquitous and constitutive promoter, CAG. These mice displayed an abnormal segmental arrangement of intersomitic vessels, while such anomalies were not observed in Tie-2p-ephrin-B2 Tg mice in which ephrin-B2 was overexpressed in only vascular endothelial cells (ECs). This finding suggests that non ECs expressing ephrin-B2 alter the migration of ECs expressing EphB receptors into the intersomitic region where ephrin-B2 expression is normally absent. CAGp-ephrin-B2 Tg mice show sudden death at neonatal stages from aortic dissecting aneurysms due to defective recruitment of vascular smooth muscle cells to the ascending aorta. Next, we investigate the role of ephrinB2 on mesenchymal cells in vascular development. To do so, we analyzed the vascular bed and network formation by para-aortic splanchnopleural mesoderm (P-Sp) explants which are rich of endothelial precursor cells from mouse embryos (E9.5) using a co-culture system with OP9 stromal cells transfected with vector or ephrin B2. Interestingly, OP9/ephrinB2 stromal cells promote both proliferation and sprouting/remodeling of ephrinB2-positive endothelial cells and smooth muscle actin-positive pericytes. These findings demonstrate that EphB/ephrin-B2 signaling between endothelial cells and surrounding mesenchymal cells plays an essential role in vasculogenesis, angiogenesis and vessel maturation. As vessel projection is initial event in many pathological condition, it may provide new strategies in (anti)-angiogenic treatment. Less

Report

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

    (21 results)

All Other

All Publications (21 results)

  • [Publications] Suda T., et al.: "Hematopoiesis and Angiogenesis"International Journal of Hematology. 71. 99-107 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Hamada K., et al.: "VEGF-C Signaling Pathways Through VEGFR-2 and VEGFR-3 in Vasculo-anglogenesis and Hematopoiesis"Blood. 96. 3793-3800 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Zhang X-Q, et al.: "Storomal Cells Expressing Ephrin B2 Promote the Growth and Sprouting of Ephrin-B2^+ Endothelial cells"Blood. 98. 1028-1037 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Shintani S., et al.: "Mobilization of Endothelial Proaenitor Cells in Patients With Acute Myocardial Infarction"Circulation. 103. 2776-2779 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Sekimoto T, et al.: "Effect of Direct Angiogenesis Inhibition in Rheumatoid Arthritis Using a Soluble Vascular Endothelial Growth Factor Receptor 1 Chimeric Protein"Journal of Rheumatology. 29. 240-245 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Yamauchi T, et al.: "Increased insulin sensitivity despite lipodystrophy in Crebbp heterozygoust mice"Nature Genetics. 30. 221-226 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Toshio Suda, Nobuyuki Takakura, Yuichi Oike: "Hematopoiesis and Angiogenesis"International Journal of Hematology. 71. 99-107 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Koichi Hamada, Yuichi Oike, Nobuyuki Takakura Yasuhiro Ito, Lotta Jussila, Daniel J. Dumont, Kari Alitalo, Toshio Suda: "VEGF-C Signaling Pathways Through VEGFR-2 and VEGFR-3 in Vasculo-angiogenesis and Hematopoiesis"Blood. 96. 3793-3800 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Xiu-Qin Zhang, Nobuyuki Takakura, Yuichi Oike, Tomohisa Inada, Nicholas W. Gale, George D. Yancopoulos, Toshio Suda: "Storomal Cells Expressing Ephrin B2 Promote the Growth and Sprouting of Ephrin-B2^+ Endothelial cells"Blood. 98. 1028-1037 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Satoshi Shintani, Toyoaki Murohara, Hisao Ikeda, Takafumi Ueno, Tomoki Honma, Atsushi Katoh, Ken-Ihiro Sasaki, Toshifumi Shimada, Yuichi Oike, Tsutomu Imaizumi: "Mobilization of Endothelial Progenitor Cells in Patients With Acute Myocardial Infarction"Circulatioin. 103. 2776-2779 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Tomohisa Sekimoto, Koichi Hamada, Yuichi Oike, Tomomi Matsuoka, Masanori Matsumoto, Etsuo Chosa, Toshio Suda, Naoya Tajima, Ken-ichi Yamamura: "Effect of Direct Angiogenesis Inhibition in Rheumatoid Arthritis Using a Soluble Vascular Endothelial Growth Factor Receptor 1 Chimeric Protein"Journal of Rheumatology. 29. 240-245 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Seiji Hokimoto, Yuichi Oike, Taro Saito, Mitsuoka Kitaoka, Shunichi Oshima, Katsuo Noda, Yasushi Moriyama, Fumiyuki Ishibashi, Hisao Ogawa: "Increased Expression of Monocyte Chemoattractant Protein-1 (MCP-1) in Atherectomy Specimens from Patients with Restenosis after Percutaneous Transluminal Coronary Angioplasty"Circulation Journal. 66. 114-116 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Toshimasa Yamauchi, Yuichi Oike, Junji Kamon, Hironori Waki, Kajuro Komeda, Atsuko Tsuchida, Yukari Date, Meng-Xian Li, Hiroshi Miki, Yasuo Akanuma, Ryozo Nagai, Satoshi Kimura, Takeyori Seheki, Masamitsu Nakazato, Takeshi Naitoh, Ken-ichi Yamamura, Takashi Kadowaki: "Increased insulin sensitivity despite lipodystrophy in Crebbp heterozygoust mice"Nature Genetics. 30. 221-226 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Suda T.et al.: "Hematopoiesis and Angiogenesis"International Journal of Hematology. 71. 99-107 (2000)

    • Related Report
      2001 Annual Research Report
  • [Publications] Hamada K. et al.: "VEGF-C Signaling Pathways Through VEGFR-2 and VEGFR-3 in Vasculo-angiogenesis and Hematopoiesis"Blood. 96. 3793-3800 (2000)

    • Related Report
      2001 Annual Research Report
  • [Publications] Zhang X-Q et al.: "Storomal Cells Expressing Ephrin B2 Promote the Growth and Sprouting of Ephrin-B2^+ Endothelial cells"Blood. 98. 1028-1037 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Shintani S. et al.: "Mobilization of Endothelial Progenitor Cells in Patients With Acute Myocardial Infarction"Circulation. 103. 2776-2779 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Sekimoto T et al.: "Effect of Direct Angiogenesis Inhibition in Rheumatoid Arthritis Using a Soluble Vascular Endothelial Growth Factor Receptor 1 Chimeric Protein"Journal of Rheumatology. 29. 240-245 (2002)

    • Related Report
      2001 Annual Research Report
  • [Publications] Yamauchi T et al.: "Increased insulin sensitivity despite lipodystrophy in Crebbp heterozygoust mice"Nature Genetics. 30. 221-226 (2002)

    • Related Report
      2001 Annual Research Report
  • [Publications] T.Suda: "Hematopoiesis and Angiogenesis"Int.J.Hemotol. 71. 99-107 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] K.Hamada: "VEGF-C Signaling Pathways Through VEGFR-2 and VEGFR-3 in Vasculo-angiogenesis and Hematopoiesis"Blood. 96. 3793-3800 (2000)

    • Related Report
      2000 Annual Research Report

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

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