Published online before print September 3, 2002, doi: 10.1161/01.HYP.0000033466.05496.89
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(Hypertension. 2002;40:451.)
© 2002 American Heart Association, Inc.
Scientific Contributions |
Effect of Estrogen and AT1 Receptor Blocker on Neointima Formation
From the Department of Medical Biochemistry (H.-W.L., M.I., Y.T.-M., L.W., J.-M.L., M.O., T.-X.C., M.H.) and Department of Obstetrics and Gynecology (Y.T.-M., M.O.), Ehime University School of Medicine, Ehime, Japan.
Correspondence to Masatsugu Horiuchi, MD, PhD, FAHA, Department of Medical Biochemistry, Ehime University School of Medicine, Shigenobu, Onsen-gun, Ehime 791-0295, Japan. E-mail horiuchi{at}m.ehime-u.ac.jp
The present study explored the possibility that estrogen may enhance the inhibitory effect of an angiotensin (Ang) II type 1 (AT1) receptor blocker on neointima formation in vascular injury, and investigated the signaling mechanism involved in their actions. Polyethylene cuff placement around the femoral artery of mice induced neointima formation and increased bromodeoxyuridine (BrdU) incorporation into vascular smooth muscle cells. These changes were significantly smaller in female mice than in male mice. Ovariectomy enhanced neointima formation and BrdU incorporation in the injured artery, which were reversed by 17ß-estradiol (80 µg/kg per day) replacement. Treatment with a selective AT1 receptor blocker, olmesartan (3 mg/kg per day), significantly inhibited neointima formation and BrdU incorporation, whereas the inhibitory effects of olmesartan were more marked in intact female mice than in male or ovariectomized mice. Phosphorylation of extracellular signal–regulated kinase (ERK), signal transducer and activator of transcription (STAT) 1, and STAT3 was increased in the injured artery. These increases were significantly smaller in intact female mice than in male or ovariectomized mice. Olmesartan or estrogen attenuated the phosphorylation of ERK and STAT in the injured artery, whereas these inhibitory effects were greater in intact female mice. Lower doses of olmesartan (0.5 mg/kg per day) or 17ß-estradiol (20 µg/kg per day) did not influence neointima formation, BrdU incorporation, and ERK and STAT phosphorylation in ovariectomized mice, whereas coadministration of olmesartan and 17ß-estradiol at these doses attenuated these parameters. These results indicate that estrogen and an AT1 receptor blocker synergistically attenuate vascular remodeling, which is at least partly via inhibition of ERK and STAT activity.
Key Words: angiotensin • estrogen • kinase • STAT • vascular remodeling
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