Effect of estrogen and AT1 receptor blocker on neointima formation.
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 17beta-estradiol (80 microg/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 17beta-estradiol (20 microg/kg per day) did not influence neointima formation, BrdU incorporation, and ERK and STAT phosphorylation in ovariectomized mice, whereas coadministration of olmesartan and 17beta-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.
D057911:Angiotensin Receptor Antagonists; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001157:Arterial Occlusive Diseases / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002316:Cardiotonic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D002455:Cell Division / Q000187:drug effects; D004247:DNA / Q000096:biosynthesis; D004268:DNA-Binding Proteins / Q000378:metabolism; D004958:Estradiol / Q000494:pharmacology* / Q000627:therapeutic use; D005260:Female; D007093:Imidazoles / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects; D000068557:Olmesartan Medoxomil; D010766:Phosphorylation / Q000187:drug effects; D044140:Receptor, Angiotensin, Type 1; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; D012737:Sex Factors; D013777:Tetrazoles / Q000494:pharmacology* / Q000627:therapeutic use; D015534:Trans-Activators / Q000378:metabolism
D057911:Angiotensin Receptor Antagonists; D000959:Antihypertensive Agents; D002316:Cardiotonic Agents; D004268:DNA-Binding Proteins; D007093:Imidazoles; D044140:Receptor, Angiotensin, Type 1; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; C494080:Stat1 protein, mouse; C494087:Stat3 protein, mouse; D013777:Tetrazoles; D015534:Trans-Activators; D004958:Estradiol; D000068557:Olmesartan Medoxomil; D004247:DNA; D020928:Mitogen-Activated Protein Kinases