title: Adrenomedullin augments collateral development in response to acute ischemia.
abstract: 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.
authors.affiliation: Department of Cardiovascular Medicine, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, 113-8655, Tokyo, Japan.
authors.forename: Minami
authors.initials: M
authors.lastname: Abe
authors.forename: Masataka
authors.initials: M
authors.lastname: Sata
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Nishimatsu
authors.forename: Daisuke
authors.initials: D
authors.lastname: Nagata
authors.forename: Etsu
authors.initials: E
authors.lastname: Suzuki
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Terauchi
authors.forename: Takashi
authors.initials: T
authors.lastname: Kadowaki
authors.forename: Naoto
authors.initials: N
authors.lastname: Minamino
authors.forename: Kenji
authors.initials: K
authors.lastname: Kangawa
authors.forename: Hisayuki
authors.initials: H
authors.lastname: Matsuo
authors.forename: Yasunobu
authors.initials: Y
authors.lastname: Hirata
authors.forename: Ryozo
authors.initials: R
authors.lastname: Nagai
mesh_terms: 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
chemical_list: 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