Pathophysiological roles of adrenomedullin' s receptor system and its potential as a therapeutical target

2010 Fiscal Year Final Research Report

• Project/Area Number: 21790713
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Single-year Grants
• Research Field: Circulatory organs internal medicine
• Research Institution: Shinshu University
• Principal Investigator: SHINDO Yuka Shinshu University, 医学系研究科, 研究員 (50507506)
• Project Period (FY): 2009 – 2010
• Keywords: アドレノメデュリン / RAMP / 血管 / 血管新生 / 血管内皮細胞

Research Abstract

Adrenomedullin (AM) is a pleiotropic peptide involved in both the pathogenesis of cardiovascular diseases and circulatory homeostasis. In the present study, we generated and analyzed knockout mice of RAMP2, a small membrane protein and a modulator of G-protein coupled receptor (GPCR), and showed that it is the key determinant of the vascular functions of AM.
To analyze the roles of vascular RAMP2 directly, we generated vascular endothelial cell-specific RAMP2 knockout mice (E-RAMP2-/-). Most E-RAMP2-/-were lethal at later-gestation with systemic edema and vascular fragility. Contrary, small number of the E-RAMP2-/-can survive. In the survived E-RAMP2-/-, the RAMP2 expression in endothelial cells was kept at 20% of wild-type littermates. In adult E-RAMP2-/-spontaneous occurrence of vasculitis lesions was detected throughout the body with aging. Furthermore, E-RAMP2-/-showed severe organ fibrosis with the enhancement of oxidative stress.
These results show that RAMP2 is the key determinant of the vascular functions of AM ; RAMP2 is essential for the vaso- and organ-protective effects of AM in adult as well as for the angiogenesis during development.

Research Products

• [Journal Article] Adrenomedullin in sinusoidal endothelial cells play protective roles against cold injury of liver. (2010)
  • Author(s): Iinuma N, Sakurai T, Kamiyoshi A, ShindoY,Arai T,Yoshizawa T, Koyama T, Uetake R, Kawate H, Muto S, Tagawa Y, Miyagawa S, Shindo T.
  • Journal Title: Peptides. 31 Pages: 865-871
  • Peer Reviewed
• [Journal Article] Endogenous a-CGRP mitigates liver fibrosis in chronic hepatitis induced by repeated administration of concanavalin A. (2009)
  • Author(s): Kamiyoshi A, Sakurai T, Shindo Y. Iinuma N, Kawate H, Yoshizawa T,Koyama T, Muto S, Shindo T.
  • Journal Title: Liver International. 29(5) Pages: 642-649
  • Peer Reviewed
• [Journal Article] Regulation of angiogenesis and vascular integrity by adrenomedullin-RAMP2 system. (2009)
  • Author(s): Shindo Y, Sakurai T, Kamiyoshi A, Koyama T, Yoshizawa T, Shindo T
  • Journal Title: 血管 32(2) Pages: 33-36
  • Peer Reviewed
• [Presentation] アドレノメデュリン-RAMP2システムは、血管新生、血管構造安定化、血管恒常性維持に必須である (2009)
  • Author(s): 新藤優佳
  • Organizer: 第82回日本内分泌学会 Young Investigator Award受賞
  • Place of Presentation: 群馬
  • Year and Date: 20090400
• [Presentation] アドレノメデュリン-RAMP2システムによる血管新生、血管恒常性維持機構 (2009)
  • Author(s): 新藤優佳
  • Organizer: 第38回日本心脈管作動物質学会 Young Investigator Award受賞
  • Place of Presentation: 岡山
  • Year and Date: 20090200
• [Remarks] ホームページ等
  • URL: http://www7a.biglobe.ne.jp/~shindo/