Vascular Endothelial Adrenomedullin-RAMP2 System Is Essential for Vascular Integrity and Organ Homeostasis
| العنوان: | Vascular Endothelial Adrenomedullin-RAMP2 System Is Essential for Vascular Integrity and Organ Homeostasis |
|---|---|
| المؤلفون: | Akihiro Yamauchi, Hisaka Kawate, Ralf H. Adams, Takayuki Shindo, Ayano Okimura, Alfredo Martínez, Nobuyoshi Iinuma, Yuka Ichikawa-Shindo, Yang Lei, Takuma Arai, Megumu Tanaka, Yasuhiro Iesato, Ryuichi Uetake, Kyoko Igarashi, Takahiro Yoshizawa, Yuichi Toriyama, Hayato Kawakami, Teruhide Koyama, Takayuki Sakurai, Akiko Kamiyoshi, Naoki Mochizuki, Laura Ochoa-Callejero |
| المصدر: | Circulation. 127:842-853 |
| بيانات النشر: | Ovid Technologies (Wolters Kluwer Health), 2013. |
| سنة النشر: | 2013 |
| مصطلحات موضوعية: | Vasculitis, Aging, Pathology, medicine.medical_specialty, Endothelium, Arteriosclerosis, Cardiac fibrosis, Kidney, Receptor Activity-Modifying Protein 2, Adrenomedullin, Mice, Antigens, CD, Fibrosis, Physiology (medical), Leukocytes, medicine, Animals, Edema, Homeostasis, Mice, Knockout, Glomerulosclerosis, Focal Segmental, business.industry, Age Factors, Kidney metabolism, Cadherins, medicine.disease, Vascular endothelial growth factor B, Disease Models, Animal, Oxidative Stress, medicine.anatomical_structure, RAMP2, Knockout mouse, Endothelium, Vascular, Cardiology and Cardiovascular Medicine, business |
| الوصف: | 信州大学博士（医学）・学位論文・平成25年3月31日授与（甲第935号）・小山 晃英 Background-Revealing the mechanisms underlying the functional integrity of the vascular system could make available novel therapeutic approaches. We previously showed that knocking out the widely expressed peptide adrenomedullin (AM) or receptor activity-modifying protein 2 (RAMP2), an AM-receptor accessory protein, causes vascular abnormalities and is embryonically lethal. Our aim was to investigate the function of the vascular AM-RAMP2 system directly. Methods and Results-We generated endothelial cell-specific RAMP2 and AM knockout mice (E-RAMP2(-/-) and E-AM(-/-)). Most E-RAMP2(-/-) mice died perinatally. In surviving adults, vasculitis occurred spontaneously. With aging, E-RAMP2(-/-) mice showed severe organ fibrosis with marked oxidative stress and accelerated vascular senescence. Later, liver cirrhosis, cardiac fibrosis, and hydronephrosis developed. We next used a line of drug-inducible E-RAMP2(-/-) mice (DI-E-RAMP2(-/-)) to induce RAMP2 deletion in adults, which enabled us to analyze the initial causes of the aforementioned vascular and organ damage. Early after the induction, pronounced edema with enhanced vascular leakage occurred. In vitro analysis revealed the vascular leakage to be caused by actin disarrangement and detachment of endothelial cells. We found that the AM-RAMP2 system regulates the Rac1-GTP/RhoA-GTP ratio and cortical actin formation and that a defect in this system causes the disruption of actin formation, leading to vascular and organ damage at the chronic stage after the gene deletion. Conclusions-Our findings show that the AM-RAMP2 system is a key determinant of vascular integrity and homeostasis from prenatal stages through adulthood. Furthermore, our models demonstrate how endothelial cells regulate vascular integrity and how their dysregulation leads to organ damage. (Circulation. 2013;127:842-853.) Article CIRCULATION. 127(7):842-853 (2013) |
| وصف الملف: | application/pdf |
| تدمد: | 1524-4539 0009-7322 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::2dea8c63213006b500bd4c5387a2e82f https://doi.org/10.1161/circulationaha.112.000756 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....2dea8c63213006b500bd4c5387a2e82f |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15244539 00097322 |
|---|