Vasoprotective Activities of the Adrenomedullin-RAMP2 System in Endothelial Cells.
Neointimal hyperplasia is the primary lesion underlying atherosclerosis and restenosis after coronary intervention. We previously described the essential angiogenic function of the adrenomedullin (AM)-receptor activity-modifying protein (RAMP) 2 system. In the present study, we assessed the vasoprotective actions of the endogenous AM-RAMP2 system using a wire-induced vascular injury model. We found that neointima formation and vascular smooth muscle cell proliferation were enhanced in RAMP2+/- male mice. The injured vessels from RAMP2+/- mice showed greater macrophage infiltration, inflammatory cytokine expression, and oxidative stress than vessels from wild-type mice and less re-endothelialization. After endothelial cell-specific RAMP2 deletion in drug-inducible endothelial cell-specific RAMP2-/- (DI-E-RAMP2-/-) male mice, we observed markedly greater neointima formation than in control mice. In addition, neointima formation after vessel injury was enhanced in mice receiving bone marrow transplants from RAMP2+/- or DI-E-RAMP2-/- mice, indicating that bone marrow-derived cells contributed to the enhanced neointima formation. Finally, we found that the AM-RAMP2 system augmented proliferation and migration of endothelial progenitor cells. These results demonstrate that the AM-RAMP2 system exerts crucial vasoprotective effects after vascular injury and could be a therapeutic target for the treatment of vascular diseases.
Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Nagano 390-8621, Japan.|Department of Pathogenic Biology, Hebei Medical University, Shijiazhuang 050017, China.
Xian
X
Xian
Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Nagano 390-8621, Japan.
Takayuki
T
Sakurai
Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Nagano 390-8621, Japan.
Akiko
A
Kamiyoshi
Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Nagano 390-8621, Japan.
Yuka
Y
Ichikawa-Shindo
Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Nagano 390-8621, Japan.
Megumu
M
Tanaka
Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Nagano 390-8621, Japan.
Teruhide
T
Koyama
Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Nagano 390-8621, Japan.
Hisaka
H
Kawate
Department of Epidemiology and Statistics, School of Public Health, Hebei Medical University, Shijiazhuang 0050017, China.
Lei
L
Yang
Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Nagano 390-8621, Japan.
Tian
T
Liu
Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Nagano 390-8621, Japan.
Akira
A
Imai
Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Nagano 390-8621, Japan.
Liuyu
L
Zhai
Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Nagano 390-8621, Japan.
Kazutaka
K
Hirabayashi
Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Nagano 390-8621, Japan.
Kun
K
Dai
Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Nagano 390-8621, Japan.
Keiya
K
Tanimura
Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Nagano 390-8621, Japan.
Teng
T
Liu
Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Nagano 390-8621, Japan.
Nanqi
N
Cui
Japan Bio Products Company, Ltd., Tokyo 151-0063, Japan.
Kyoko
K
Igarashi
Japan Bio Products Company, Ltd., Tokyo 151-0063, Japan.
Akihiro
A
Yamauchi
Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Nagano 390-8621, Japan.
Takayuki
T
Shindo
D053607:Adrenomedullin / Q000235:genetics / Q000502:physiology*; D000818:Animals; D002478:Cells, Cultured; D019610:Cytoprotection / Q000235:genetics*; D042783:Endothelial Cells / Q000502:physiology*; D005263:Femoral Artery / Q000293:injuries / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D058426:Neointima / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D058263:Receptor Activity-Modifying Protein 2 / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000235:genetics; D057772:Vascular System Injuries / Q000235:genetics / Q000517:prevention & control*
C545506:Ramp2 protein, mouse; D058263:Receptor Activity-Modifying Protein 2; D053607:Adrenomedullin