Adrenomedullin augments collateral development in response to acute ischemia.
Expression of adrenomedullin, discovered as a vasodilatory peptide, is markedly up-regulated under pathological conditions such as tissue ischemia and inflammation, which are associated with neovascularization. Here, we tested the hypothesis that overly expressed adrenomedullin may augment collateral flow to ischemic tissues. We induced hindlimb ischemia in wild-type mice and injected a naked plasmid expressing human adrenomedullin or an empty vector into the ischemic muscle, followed by in vivo electroporation. Adrenomedullin markedly enhanced blood flow recovery as determined by Laser Doppler imaging. The mice treated with an empty vector suffered frequent autoamputation of the ischemic toe, which was completely prevented by adrenomedullin. Anti-CD31 immunostaining revealed that adrenomedullin significantly increased capillary density. The angiogenic effect of adrenomedullin was abrogated in endothelial nitric oxide synthase (eNOS)-deficient mice. These results indicate that adrenomedullin may promote collateral growth in response to ischemia through activation of eNOS.
Abe
Minami
M
Department of Cardiovascular Medicine, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, 113-8655, Tokyo, Japan.
Sata
Masataka
M
Nishimatsu
Hiroaki
H
Nagata
Daisuke
D
Suzuki
Etsu
E
Terauchi
Yasuo
Y
Kadowaki
Takashi
T
Minamino
Naoto
N
Kangawa
Kenji
K
Matsuo
Hisayuki
H
Hirata
Yasunobu
Y
Nagai
Ryozo
R
D000208:Acute Disease; D053607:Adrenomedullin; D000818:Animals; D003097:Collateral Circulation / Q000187:drug effects / Q000502:physiology*; D005260:Female; D015870:Gene Expression; D018014:Gene Transfer Techniques; D006801:Humans; D007511:Ischemia / Q000235:genetics / Q000503:physiopathology* / Q000628:therapy*; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018919:Neovascularization, Physiologic; D009569:Nitric Oxide / Q000502:physiology; D019001:Nitric Oxide Synthase / Q000172:deficiency / Q000235:genetics; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D010455:Peptides / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D011994:Recombinant Proteins / Q000235:genetics; D014664:Vasodilation / Q000187:drug effects
D010455:Peptides; D011994:Recombinant Proteins; D053607:Adrenomedullin; D009569:Nitric Oxide; C496314:NOS3 protein, human; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse