Methoxyestradiols Mediate the Antimitogenic Effects of 17 β-Estradiol: Direct Evidence from Catechol-O-Methyltransferase-Knockout Mice

Lefteris C. Zacharia, Joseph A. Gogos, Maria Karayiorgou, Edwin K. Jackson, Delbert G. Gillespie, Federica Barchiesi, Raghvendra K. Dubey

Research output: Contribution to journalArticlepeer-review

43 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)2974-2978
Number of pages5
JournalCirculation
Volume108
Issue number24
DOIs
Publication statusPublished - 16 Dec 2003

Keywords

  • Coronary disease
  • Hormones
  • Metabolism
  • Muscle, smooth
  • Receptors

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