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Molecular mechanism of vascular endothelial/mural cell differentiation by receptor tyrosine kinases

Research Project

Project/Area Number 15570110
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Functional biochemistry
Research InstitutionThe University of Tokyo

Principal Investigator

MIYAZAWA Keiji  The University of Tokyo, Graduate School of Medicine, Associate Professor, 大学院・医学系研究科, 助教授 (40209896)

Co-Investigator(Kenkyū-buntansha) WATABE Tetsuro  The University of Tokyo, Graduate School of Medicine, Research Associate, 大学院・医学系研究科, 助手 (00334235)
Project Period (FY) 2003 – 2004
Project Status Completed (Fiscal Year 2004)
Budget Amount *help
¥3,700,000 (Direct Cost: ¥3,700,000)
Fiscal Year 2004: ¥1,400,000 (Direct Cost: ¥1,400,000)
Fiscal Year 2003: ¥2,300,000 (Direct Cost: ¥2,300,000)
Keywordsendothelial cells / mural cells / tyrosine kinase / growth factors / differentiation / リンパ管内皮細胞 / 平滑筋細胞
Research Abstract

In the present study, we examined the roles of receptor tyrosine kinases in differentiation of mouse embryonic stem (ES) cell-derived VEGFR2^+ cells into endothelial cells and mural cells.
(1)VEGFR3 signaling in endothelial differentiation
VEGFR3 is a receptor for VEGF-C and VEGF-D. In order to examine the role of VEGFR3 in endothelial differentiation, we established ES cells expressing VEGFR3 by Supertransfection technique and then prepared VEGFR2^+ cells through in vitro differentiation and MACS. These cells differentiated into endothelial cells and expressed lymphatic endothelial marker LYVE-1 in the presence of VEGF-C. VEGF-C stimulates VEGFR3 as well as VEGFR3, whereas VEGF-C (C152S) mutant exclusively stimulates VEGFR3. VEGF-C (C152S) failed to induce endothelial differentiation. Upon stimulation with VEGF-C, VEGFR2 signaling is indispensable for endothelial differentiation, and VEGFR3 signaling additionally confers lymphatic endothelial-like phenotypes to endothelial cells.
(2)FGF signaling in endothelial/smooth muscle differentiation
We examined the differentiation of VEGFR2^+ cells in the presence of FGF-2 for 2 days. 45% of the cells differentiated PECAM1^+ endothelial cells, 20% of them differentiated into SMA^+ mural cells, and 35% of them remained negative for both markers. FGF-2 thus does not direct cell differentiation to one specific lineage. We also examined the co-stimulatory effect of VEGF-A and FGF-2. Whereas VEGF-A caused exclusive endothelial differentiation, VEGF-A/FGF-2 co-stimulation induced 95% endothelial cells and 5% mural cells. Notably mural cells attached to the entdothelial sheets. We found that the cell-cell communication was mediated through endogenonus PDGF-B/PDGFRβ signaling.

Report

(3 results)
  • 2004 Annual Research Report   Final Research Report Summary
  • 2003 Annual Research Report
  • Research Products

    (6 results)

All 2005 2003 Other

All Journal Article (5 results) Publications (1 results)

  • [Journal Article] Roles of vascular endothelial growth factor receptor 3 signaling in differentiation of mouse embryonic stem cell-derived vascular progenitor cells into endothelial cells2005

    • Author(s)
      Suzuki et al.
    • Journal Title

      Blood 105

      Pages: 2372-2379

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Roles of vascular endothelial growth factor receptor 3 signaling in differentiation of mouse embryonic stem cell-derived vascular progenitor cells into endothelial cells.2005

    • Author(s)
      Suzuki, H. et al.
    • Journal Title

      Blood 105

      Pages: 2372-2379

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Roles of vascular endothelial growth factor receptor 3 signaling in differentiation of mouse embryonic stem cell-derived vascular progenitor cells into endothelial cells2005

    • Author(s)
      Suzuki et al.
    • Journal Title

      Blood 205

      Pages: 2372-2379

    • Related Report
      2004 Annual Research Report
  • [Journal Article] TGF-β receptor kinase inhibitor enhances growth and integrity of embryonic stem cell-derived endothelial cells2003

    • Author(s)
      Watabe et al.
    • Journal Title

      J.Cell Biol. 163

      Pages: 1303-1311

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] TGF-β receptor kinase inhibitor enhances growth and integrity of embryonic stem cell-derived endothelial cells.2003

    • Author(s)
      Watabe, T. et al.
    • Journal Title

      J.Cell Biol. 163

      Pages: 1303-1311

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Publications] Watanabe et al.: "TGF-β receptor kinase inhibitor enhances growth and integrity of embryonic stem cell-derived endothelial cells"J.Cell Biol.. 163. 1303-1311 (2003)

    • Related Report
      2003 Annual Research Report

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Published: 2003-04-01   Modified: 2016-04-21  

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