| First Author | Zacharia LC | Year | 2003 |
| Journal | Circulation | Volume | 108 |
| Issue | 24 | Pages | 2974-8 |
| PubMed ID | 14662705 | Mgi Jnum | J:323304 |
| Mgi Id | MGI:7262808 | Doi | 10.1161/01.CIR.0000106900.66354.30 |
| Citation | Zacharia LC, et al. (2003) Methoxyestradiols mediate the antimitogenic effects of 17beta-estradiol: direct evidence from catechol-O-methyltransferase-knockout mice. Circulation 108(24):2974-8 |
| abstractText | BACKGROUND: Studies using pharmacological agents suggest but do not prove that the antimitogenic effects of estradiol are caused by conversion of estradiol to hydroxyestradiols (mediated by CYP450s) followed by methylation of hydroxyestradiols to methoxyestradiols (mediated by catechol-O-methyltransferase, COMT). METHODS AND RESULTS: To test this hypothesis more rigorously, we used aortic smooth muscle cells (SMCs) from mice lacking COMT (COMT-KO). Wild-type (WT) but not COMT-KO SMCs efficiently converted 2-hydroxyestradiol to 2-methoxyestradiol. Both WT and COMT-KO SMCs expressed estrogen receptors. Estradiol and 2-hydroxyestradiol concentration-dependently inhibited serum-induced DNA synthesis, cell numbers, and collagen synthesis in WT but not COMT-KO SMCs. 2-Methoxyestradiol inhibited DNA synthesis, cell numbers, and collagen synthesis in both WT and COMT-KO SMCs. CONCLUSIONS: These data provide strong evidence that the vascular antimitogenic effects of estradiol are estrogen receptor-independent and involve the sequential conversion of estradiol to hydroxyestradiols and then to methoxyestradiols. |
