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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2002;22:1310.)
© 2002 American Heart Association, Inc.

Vascular Biology

Resistance to Neointimal Hyperplasia and Fatty Streak Formation in Mice With Adrenomedullin Overexpression

Yasushi Imai; Takayuki Shindo; Koji Maemura; Masataka Sata; Yuichiro Saito; Yukiko Kurihara; Masahiro Akishita; Junichi Osuga; Shun Ishibashi; Kazuyuki Tobe; Hiroyuki Morita; Yoshio Oh-hashi; Toru Suzuki; Hiromitsu Maekawa; Kenji Kangawa; Naoto Minamino; Yoshio Yazaki; Ryozo Nagai; Hiroki Kurihara

From the Department of Cardiovascular Medicine (Y.I., T. Shindo, K.M., M.S., Y.K., H. Morita, Y.O., T. Suzuki, H. Maekawa, R.N.) and the Department of Metabolic Diseases (J.O., S.I., K.T.), Graduate School of Medicine, The University of Tokyo, Tokyo; the 2nd Department of Internal Medicine (Y.S.), School of Medicine, Gunma University, Maebashi; the Department of Geriatric Medicine (M.A.), School of Medicine, Kyorin University, Tokyo; The National Cardiovascular Center Research Institute (K.K., N.M.), Suita; the International Medical Center of Japan (Y.Y.), Tokyo; and the Division of Integrative Cell Biology (H.K.), Department of Embryogenesis, Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto, Japan.

Correspondence to Hiroki Kurihara, MD, PhD, Division of Integrative Cell Biology, Department of Embryogenesis, Institute of Molecular Embryology and Genetics, Kumamoto University, 2-2-1 Honjo, Kumamoto 860-0811, Japan. E-mail kurihara{at}kaiju.medic.kumamoto-u.ac.jp

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).

Methods and 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-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.

Key Words: adrenomedullin • transgenic mice • neointimal hyperplasia • fatty streak • apolipoprotein E knockout mice

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