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

Circulation (New York, N.Y.), 2013-02, Vol.127 (7), p.842-853 [Peer Reviewed Journal]

2014 INIST-CNRS ;ISSN: 0009-7322 ;EISSN: 1524-4539 ;DOI: 10.1161/circulationaha.112.000756 ;PMID: 23355623 ;CODEN: CIRCAZ

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Title:
Vascular Endothelial Adrenomedullin-RAMP2 System Is Essential for Vascular Integrity and Organ Homeostasis
Author: KOYAMA, Teruhide ; OCHOA-CALLEJERO, Laura ; UETAKE, Ryuichi ; OKIMURA, Ayano ; YAMAUCHI, Akihiro ; TANAKA, Megumu ; IGARASHI, Kyoko ; TORIYAMA, Yuichi ; KAWATE, Hisaka ; ADAMS, Ralf H ; KAWAKAMI, Hayato ; MOCHIZUKI, Naoki ; SAKURAI, Takayuki ; MARTINEZ, Alfredo ; SHINDO, Takayuki ; KAMIYOSHI, Akiko ; ICHIKAWA-SHINDO, Yuka ; IINUMA, Nobuyoshi ; ARAI, Takuma ; YOSHIZAWA, Takahiro ; IESATO, Yasuhiro ; YANG LEI
Subjects: Adrenomedullin - metabolism ; Age Factors ; Aging - metabolism ; Animals ; Antigens, CD - genetics ; Antigens, CD - metabolism ; Arteriosclerosis - metabolism ; Arteriosclerosis - pathology ; Arteriosclerosis - physiopathology ; Atherosclerosis (general aspects, experimental research) ; Biological and medical sciences ; Blood and lymphatic vessels ; Cadherins - genetics ; Cadherins - metabolism ; Cardiology. Vascular system ; Disease Models, Animal ; Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous ; Edema - metabolism ; Edema - pathology ; Edema - physiopathology ; Endothelium, Vascular - metabolism ; Endothelium, Vascular - pathology ; Endothelium, Vascular - physiopathology ; Fibrosis - metabolism ; Fibrosis - pathology ; Fibrosis - physiopathology ; Glomerulosclerosis, Focal Segmental - metabolism ; Glomerulosclerosis, Focal Segmental - pathology ; Glomerulosclerosis, Focal Segmental - physiopathology ; Homeostasis - physiology ; Kidney - metabolism ; Kidney - pathology ; Kidney - physiopathology ; Leukocytes - metabolism ; Medical sciences ; Mice ; Mice, Knockout ; Oxidative Stress - physiology ; Receptor Activity-Modifying Protein 2 - genetics ; Receptor Activity-Modifying Protein 2 - metabolism ; Vasculitis - metabolism ; Vasculitis - pathology ; Vasculitis - physiopathology
Is Part Of: Circulation (New York, N.Y.), 2013-02, Vol.127 (7), p.842-853
Description: 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. 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. 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.
Publisher: Hagerstown, MD: Lippincott Williams & Wilkins
Language: English
Identifier: ISSN: 0009-7322
EISSN: 1524-4539
DOI: 10.1161/circulationaha.112.000756
PMID: 23355623
CODEN: CIRCAZ
Source: GFMER Free Medical Journals
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Vascular Endothelial Adrenomedullin-RAMP2 System Is Essential for Vascular Integrity and Organ Homeostasis

2014 INIST-CNRS ;ISSN: 0009-7322 ;EISSN: 1524-4539 ;DOI: 10.1161/circulationaha.112.000756 ;PMID: 23355623 ;CODEN: CIRCAZ

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