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  1. 050 医学部, 大学院医学系研究科
  2. 0507 学位論文
  3. 博士(医学)

Vascular Endothelial Adrenomedullin-RAMP2 System Is Essential for Vascular Integrity and Organ Homeostasis

http://hdl.handle.net/10091/17664
4354d1c7-7b4b-4f54-be2a-63084ea15f98
名前 / ファイル ライセンス アクション
H24Kou935_Koyama.pdf H24Kou935_Koyama.pdf (3.9 MB)
Item type 学術雑誌論文 / Journal Article(1)
公開日 2014-06-27
タイトル
タイトル Vascular Endothelial Adrenomedullin-RAMP2 System Is Essential for Vascular Integrity and Organ Homeostasis
言語
言語 eng
資源タイプ
資源 http://purl.org/coar/resource_type/c_6501
タイプ journal article
著者 Koyama, Teruhide

× Koyama, Teruhide

WEKO 17302

Koyama, Teruhide

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Ochoa-Callejero, Laura

× Ochoa-Callejero, Laura

WEKO 17303

Ochoa-Callejero, Laura

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Sakurai, Takayuki

× Sakurai, Takayuki

WEKO 17304

Sakurai, Takayuki

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Kamiyoshi, Akiko

× Kamiyoshi, Akiko

WEKO 17305

Kamiyoshi, Akiko

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Ichikawa-Shindo, Yuka

× Ichikawa-Shindo, Yuka

WEKO 17306

Ichikawa-Shindo, Yuka

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Iinuma, Nobuyoshi

× Iinuma, Nobuyoshi

WEKO 17307

Iinuma, Nobuyoshi

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Arai, Takuma

× Arai, Takuma

WEKO 17308

Arai, Takuma

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Yoshizawa, Takahiro

× Yoshizawa, Takahiro

WEKO 17309

Yoshizawa, Takahiro

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Iesato, Yasuhiro

× Iesato, Yasuhiro

WEKO 17310

Iesato, Yasuhiro

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Lei, Yang

× Lei, Yang

WEKO 17311

Lei, Yang

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Uetake, Ryuichi

× Uetake, Ryuichi

WEKO 17312

Uetake, Ryuichi

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Okimura, Ayano

× Okimura, Ayano

WEKO 17313

Okimura, Ayano

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Yamauchi, Akihiro

× Yamauchi, Akihiro

WEKO 17314

Yamauchi, Akihiro

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Tanaka, Megumu

× Tanaka, Megumu

WEKO 17315

Tanaka, Megumu

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Igarashi, Kyoko

× Igarashi, Kyoko

WEKO 17316

Igarashi, Kyoko

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Toriyama, Yuichi

× Toriyama, Yuichi

WEKO 17317

Toriyama, Yuichi

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Kawate, Hisaka

× Kawate, Hisaka

WEKO 17318

Kawate, Hisaka

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Adams, Ralf H.

× Adams, Ralf H.

WEKO 17319

Adams, Ralf H.

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Kawakami, Hayato

× Kawakami, Hayato

WEKO 17320

Kawakami, Hayato

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Mochizuki, Naoki

× Mochizuki, Naoki

WEKO 17321

Mochizuki, Naoki

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Martinez, Alfredo

× Martinez, Alfredo

WEKO 17322

Martinez, Alfredo

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Shindo, Takayuki

× Shindo, Takayuki

WEKO 17323

Shindo, Takayuki

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出版者
出版者 LIPPINCOTT WILLIAMS & WILKINS
引用
内容記述タイプ Other
内容記述 CIRCULATION. 127(7):842-853 (2013)
書誌情報 CIRCULATION

巻 127, 号 7, p. 842-853, 発行日 2013-02
内容記述
内容記述タイプ Other
内容記述 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
抄録
内容記述タイプ Abstract
内容記述 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.)
資源タイプ(コンテンツの種類)
内容記述タイプ Other
内容記述 Article
DOI
関連識別子
識別子タイプ DOI
関連識別子 http://dx.doi.org/10.1161/CIRCULATIONAHA.112.000756
関連名称
関連名称 10.1161/CIRCULATIONAHA.112.000756
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