| Project/Area Number |
10470227
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Endocrinology
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| Research Institution | KYOTO UNIVERSITY |
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Principal Investigator |
ITOH Hiroshi Kyoto University Graduate School of Medicine, Medicine and Clinical Science, Assistant Professor, 医学研究科, 助手 (40252457)
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| Co-Investigator(Kenkyū-buntansha) |
HOSODA Kiminori Hosoda, Kiminori Kyoto University, Graduate School of human and Environment Studies, Assistant Professor, 人間・環境学研究科, 助手 (40271598)
UMEMURA Kazuo Hamamatsu University of Medicine, Professor, 医学部, 教授 (40232912)
OGAWA Minetaro Kyoto University Graduate School of Medicine, Medicine and Clinical Science, Assistant Professor, 医学研究科, 助手 (70194454)
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| Project Period (FY) |
1998 – 1999
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| Project Status |
Completed (Fiscal Year 1999)
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| Budget Amount *help |
¥7,600,000 (Direct Cost: ¥7,600,000)
Fiscal Year 1999: ¥3,000,000 (Direct Cost: ¥3,000,000)
Fiscal Year 1998: ¥4,600,000 (Direct Cost: ¥4,600,000)
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| Keywords | endothelial cells / vascular smooth muscle cells / natriuretic peptides / ES cells / atherosclerosis / VEGF / transgenic mice / adenovirus / cGMP / 前駆細胞 |
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| Research Abstract |
Endothelial dysfunction plays the pivotal role in proliferative vascular diseases. Molecular understanding of endothelial cell function leads to vascular regeneration therapy. This research project aims at elucidation of the pathophygiological significance of vascular local hormones, especially natriuretic peptides, mainly by the approach of developmental cell biology.
1. We demonstrated that VEGF (vascular endothelial growth factor) modulates endothelial secretion of vascular local hormones, including CNP (C-type natriuretic peptide) and reported that VEGF expression is augmented in human coronary atherosclerotic lesions. VEGF and its receptor (Flk-1,flt-1) expression were detected in activated endothelial cells, de-differentiated vascular smooth muscle cells and macrophages. Oxidized LDL up-regulated VEGF expression in cultured human coronary endothelial cells.
2. Using cell sorting technique, we isolated Flk-1 positive mouse ES cells, cultured them on collagen IV coated dishes with VEGF and made them differentiated into endothelial cells. In collagen gel 3D culture, we also succeeded in tube formation with Flk-1 ES cells. We also clarified the gene expression of CNP and its receptor, Guanylate Cyclase B during the course of differentiation of ES cells to embryoid body. We reported CNP expression in rat embryo and neonatal lung tissue.
3. We constructed CNP cDNA recombinant adenovirus and using the CNP adenovirus demonstrated that over-expression of CNP in balloon-injured rabbit femoral artery resulted in suppression of neointimal formation, re-differentiation of vascular smooth muscle cells and acceleration of re-endothelialization. We also succeeded in cloning human cGMP-dependent protein kinase(cGK)type Iα and developed cGK transgenic mice(cGK. Tg). In cGK. Tg, strong cGK expression was detected in the brain, heart, blood vessels and skeletal muscle. Using the cGK. Tg, we demonstrated that cGK can act for vascular protection in photo-chemical injury model.
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