| Project/Area Number |
15200034
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| Research Category |
Grant-in-Aid for Scientific Research (A)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Biomedical engineering/Biological material science
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| Research Institution | The University of Tokyo |
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Principal Investigator |
ANDO Joji The University of Tokyo, Graduate School of Medicine, Professor, 大学院・医学系研究科, 教授 (20159528)
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| Co-Investigator(Kenkyū-buntansha) |
YAMAMOTO Kimiko The University of Tokyo, Graduate School of Medicine, lecturer, 大学院・医学系研究科, 講師 (00323618)
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| Project Period (FY) |
2003 – 2005
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| Project Status |
Completed (Fiscal Year 2005)
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| Budget Amount *help |
¥50,310,000 (Direct Cost: ¥38,700,000、Indirect Cost: ¥11,610,000)
Fiscal Year 2005: ¥10,920,000 (Direct Cost: ¥8,400,000、Indirect Cost: ¥2,520,000)
Fiscal Year 2004: ¥10,920,000 (Direct Cost: ¥8,400,000、Indirect Cost: ¥2,520,000)
Fiscal Year 2003: ¥28,470,000 (Direct Cost: ¥21,900,000、Indirect Cost: ¥6,570,000)
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| Keywords | Shear Stress / Blood Flow / Mechanotransduction / DNA Microarray / Endothelial Cells / Blood Vessels / P2X4 Receptor / Calcium Ion / 剪断能力 / 遺伝子 / 血管リモデリング / 血行力学因子 / DNAチップ / 粥状動脈硬化 / 剪断応力 |
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| Research Abstract |
To elucidate the role of shear stress, a mechanical force generated by flowing blood, in the regulation of circulatory functions, we investigated the mechanism by which vascular endothelial cells sense shear stress and performed a global analysis of shear stress-responsive genes. The present study showed that endothelial cells transduce shear stress intensity into extracellular Ca^<2+> influx via an ATP-operated cation channel P2X4. We produced P2X4-deficient mice and observed that endothelial cells of P2X4-deficient mice did not show shear stress-induced Ca^<2+> influx and subsequent production of nitric oxide. Compared with wild-type mice, P2X4-deficient mice showed impaired vasodilatory responses to an increase in blood flow, and higher values of blood pressure. P2X4-deficient mice also showed impaired blood flow-dependent vascular remodeling. These findings indicate that the P2X4-mediated shear stress-sensing mechanism plays a critical role in blood flow-dependent control of circulatory functions. DNA micro-array analysis revealed that approximately 3% of the total endothelial genes alter their expression in response to an arterial level of shear stress (15 dynes/cm^2), indicating that about 600 genes are shear stress-responsive. Cluster analysis showed multiple temporal profiles of gene responses to shear stress. We also demonstrated that endothelial gene expression is differentially regulated by laminar and turbulent shear stress. Laminar shear stress decreased the gene expression of urokinase-type plasminogen activator (uPA) via down-regulating gene transcription and accelerating mRNA degradation, while turbulent shear stress increased uPA gene expression through mRNA stabilization.
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