Effects of adrenomedullin on acute ischaemia-induced collateral development and mobilization of bone-marrow-derived cells.
Adrenomedullin exerts not only vasodilatory effects, but also angiogenic effects. In the present study, we investigated the effects of adrenomedullin on collateral formation and circulating bone-marrow-derived cells after acute tissue ischaemia. Bone marrow of 8-10-week-old female C57BL/6J mice was replaced with that from GFP (green fluorescent protein) transgenic mice (GFP mice). At 8 weeks after transplantation, hindlimb ischaemia was induced by resecting the right femoral artery and a plasmid expressing human adrenomedullin (50 mug) was injected into the ischaemic muscle, followed by in vivo electroporation on a weekly basis. Overexpression of adrenomedullin significantly enhanced the blood flow recovery compared with controls (blood flow ratio, 1.0+/-0.2 compared with 0.6+/-0.3 respectively, at week 4; P<0.05) and increased capillary density in the ischaemic leg as determined by anti-CD31 immunostaining of the ischaemic muscle (567+/-40 compared with 338+/-65 capillaries/mm(2) respectively, at week 5; P<0.05). There were more GFP-positive cells in the thigh muscle of the mice injected with adrenomedullin than in that of the control mice (29.6+/-4.5 compared with 16.5+/-3.3 capillaries/mm(2) respectively, at week 5; P<0.05). We repeated the same experiments using LacZ-knock-in mice instead of GFP mice, and obtained similar results. These findings suggest that adrenomedullin may augment ischaemia-induced collateral formation with some effects on circulating bone-marrow-derived cells.
Abe
Minami
M
Department of Cardiovascular Medicine, University of Tokyo Graduate School of Medicine, Tokyo, Japan.
Sata
Masataka
M
Suzuki
Etsu
E
Takeda
Ryo
R
Takahashi
Masao
M
Nishimatsu
Hiroaki
H
Nagata
Daisuke
D
Kangawa
Kenji
K
Matsuo
Hisayuki
H
Nagai
Ryozo
R
Hirata
Yasunobu
Y
D053607:Adrenomedullin / Q000494:pharmacology*; D000818:Animals; D016026:Bone Marrow Transplantation; D003097:Collateral Circulation / Q000187:drug effects*; D005260:Female; D005434:Flow Cytometry; D049452:Green Fluorescent Proteins / Q000378:metabolism; D019650:Hematopoietic Stem Cell Mobilization; D006412:Hematopoietic Stem Cells / Q000187:drug effects*; D006614:Hindlimb / Q000098:blood supply; D007511:Ischemia / Q000503:physiopathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018482:Muscle, Skeletal / Q000098:blood supply; D014665:Vasodilator Agents / Q000494:pharmacology*
D014665:Vasodilator Agents; D049452:Green Fluorescent Proteins; D053607:Adrenomedullin