Vascular endothelial adrenomedullin-RAMP2 system is essential for vascular integrity and organ homeostasis.
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.


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.
Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Asahi 3-1-1, Matsumoto, Nagano, 390-8621, Japan.
Teruhide
T
Koyama
Laura
L
Ochoa-Callejero
Takayuki
T
Sakurai
Akiko
A
Kamiyoshi
Yuka
Y
Ichikawa-Shindo
Nobuyoshi
N
Iinuma
Takuma
T
Arai
Takahiro
T
Yoshizawa
Yasuhiro
Y
Iesato
Yang
Y
Lei
Ryuichi
R
Uetake
Ayano
A
Okimura
Akihiro
A
Yamauchi
Megumu
M
Tanaka
Kyoko
K
Igarashi
Yuichi
Y
Toriyama
Hisaka
H
Kawate
Ralf H
RH
Adams
Hayato
H
Kawakami
Naoki
N
Mochizuki
Alfredo
A
Martínez
Takayuki
T
Shindo
D053607:Adrenomedullin / Q000378:metabolism*; D000367:Age Factors; D000375:Aging / Q000378:metabolism; D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism; D001161:Arteriosclerosis / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D004487:Edema / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D004730:Endothelium, Vascular / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D005355:Fibrosis / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D005923:Glomerulosclerosis, Focal Segmental / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D006706:Homeostasis / Q000502:physiology*; D007668:Kidney / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D007962:Leukocytes / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D018384:Oxidative Stress / Q000502:physiology; D058263:Receptor Activity-Modifying Protein 2 / Q000235:genetics / Q000378:metabolism*; D014657:Vasculitis / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D000099152:Cadherin 5
D053607:Adrenomedullin; D015703:Antigens, CD; D015820:Cadherins; D058263:Receptor Activity-Modifying Protein 2; D000099152:Cadherin 5; C545506:Ramp2 protein, mouse