| Project/Area Number |
12835011
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Institution | Kumamoto University |
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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)
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| 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)
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| Project Period (FY) |
2000 – 2001
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| Project Status |
Completed (Fiscal Year 2001)
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| 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)
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| Keywords | Vasculogenesis / 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 |
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| 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
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-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
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