Resistance to neointimal hyperplasia and fatty streak formation in mice with adrenomedullin overexpression.
OBJECTIVE
Several in vitro studies have implicated that adrenomedullin (AM) plays an important role in the pathogenesis of vascular injury and fatty streak formation. To test this possibility in vivo, we evaluated 2 experimental models using transgenic mice overexpressing AM in a vessel-selective manner (AMTg mice).


RESULTS
Placement of a periarterial cuff on femoral arteries resulted in neointimal formation at 2 to 4 weeks to a lesser extent in AMTg mice than in their wild-type littermates (at 28 days, intima/media area ratio 0.45+/-0.14 versus 1.31+/-0.41, respectively; P<0.001). This vasculoprotective effect observed in AMTg mice was inhibited by N(omega)-nitro-L-arginine methyl ester. We further examined the effect of AM on hypercholesterolemia-induced fatty streak formation by crossing AMTg mice with apolipoprotein E knockout mice (ApoEKO mice). The extent of the formation of fatty streak lesions was significantly less in ApoEKO/AMTg mice than in ApoEKO mice (percent lesion area 12.0+/-3.9% versus 15.8+/-2.8%, respectively; P<0.05). Moreover, endothelium-dependent vasodilatation as indicative of NO production was superior in AMTg/ApoEKO mice compared with ApoEKO mice.


CONCLUSIONS
Taken together, our data demonstrated that AM possesses a vasculoprotective effect in vivo, which is at least partially mediated by NO.
Imai
Yasushi
Y
Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
Shindo
Takayuki
T
Maemura
Koji
K
Sata
Masataka
M
Saito
Yuichiro
Y
Kurihara
Yukiko
Y
Akishita
Masahiro
M
Osuga
Junichi
J
Ishibashi
Shun
S
Tobe
Kazuyuki
K
Morita
Hiroyuki
H
Oh-hashi
Yoshio
Y
Suzuki
Toru
T
Maekawa
Hiromitsu
H
Kangawa
Kenji
K
Minamino
Naoto
N
Yazaki
Yoshio
Y
Nagai
Ryozo
R
Kurihara
Hiroki
H
D000273:Adipose Tissue / Q000378:metabolism*; D053607:Adrenomedullin; D000818:Animals; D001057:Apolipoproteins E / Q000378:metabolism; D015740:Calcitonin Gene-Related Peptide / Q000494:pharmacology; D005263:Femoral Artery / Q000378:metabolism / Q000473:pathology; D006830:Hydralazine / Q000494:pharmacology; D006965:Hyperplasia / Q000517:prevention & control; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism; D010446:Peptide Fragments / Q000494:pharmacology; D010455:Peptides / Q000378:metabolism*; D017539:Tunica Intima / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*
D001057:Apolipoproteins E; D010446:Peptide Fragments; D010455:Peptides; C058636:calcitonin gene-related peptide (8-37); D053607:Adrenomedullin; D006830:Hydralazine; D009569:Nitric Oxide; D015740:Calcitonin Gene-Related Peptide; D019331:NG-Nitroarginine Methyl Ester