| Project/Area Number |
18590366
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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 Field |
Experimental pathology
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| Research Institution | Shinshu University |
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Principal Investigator |
SAKURAI Takayuhi Shinshu University, Graduate School of Medicine, associate professor (80317825)
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| Co-Investigator(Kenkyū-buntansha) |
SHINDO Takayuki Shinshu Univ, Graduate School of Medicine, professor (90345215)
SATO Masahiro Kagoshima Univ, Fronter Science Research Center, professor (30287099)
SHIMOSAWA Tatsuo Univ. of Tokyo, Fac. of Med.Dep of Int Med, Lecturer (90231365)
NAGAYA Noritoshi The Nat Cardiovas.Ceter Res, Institute, Director (60372116)
KANGAWA Kenji The Nat Cardiovas.Ceter Res, Institute, President (00112417)
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| Project Period (FY) |
2006 – 2007
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| Project Status |
Completed (Fiscal Year 2007)
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| Budget Amount *help |
¥4,010,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥510,000)
Fiscal Year 2007: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
Fiscal Year 2006: ¥1,800,000 (Direct Cost: ¥1,800,000)
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| Keywords | Adrenomedullin / receptor activity-modifying Protein / vasodilatineg peptide / chimera / mouse / angiogenesis / lvmphangiogenesis / disease-model animal |
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| Research Abstract |
Adrenomedullin (AM) is a multifimctional peptide involved in cardiovascular disease. The AM receptor is composed of receptor activity-modifying protein 2 or 3(RAMP2 or 3) and calcitonin receptor-like receptor. We has demonstrated that AM-RAMP2 signal is essential for vascular integrity and normal growth, since both AM and RAMP2 null embryo have severe edema and hemorrhage and are lethal at E12.5-E14.5 due to vascular abnormalities.
To extend these observations, we generated chimeric mice that were made by aggregating between wild-type (+1+, lacZ/+) and AM or RAMP2 (-/-, +/+) 8 cell-embryo, or between wild-type (+/+, +/+) and AM or RAMP2 (-/-, lacZ/+) 8 cell-embryo. The genotype of chimeras was determined by our real time-genomic PCR (Sakurai, et. al.,2008). The resulting chimeras including -/- cells displayed edema, and were alive until around E16.0. It was observed that the network of blood and lymphatic vessels of the chimeric organs including liver and lung tended to be weak compared with those of wild type-organs using immunohistochemical staining of anti-CD31 (as an endothelial cell marker) and anti-lyve-1 (as an lymphatic vessel marker). We also showed that both -/- cell and +/+ cell- regions of the chimeric yolk sac had vascular defects, indicating AM-RAMP2 signal contributes to angiogenesis in yolk sac in a non-autonomous way. The -/- <-> +/+ chimeric embryo would become dysfunctional because of these phenotypes of blood and lymphatic vessels, resulting in embryonic lethal. Accordingly, in this study, our results demonstrate that the robust role of AM-RAMP2 signal is angiogenesis and lymphangiogenesis during embryogenesis and the signal is also necessary during organogenesis.
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