Catecholamines block the antimitogenic effect of estradiol on human coronary artery smooth muscle cells

Raghvendra K. Dubey, Edwin K. Jackson, Delbert G. Gillespie, Lefteris C. Zacharia, Bruno Imthurn

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Abstract

Sequential conversion of estradiol to catecholestradiols and methoxyestradiols by cytochrome-P 450 (CYP450) and catechol-O-methyltransferase (COMT), respectively, contributes to the antimitogenic effects of estradiol on vascular smooth muscle cell (SMC) growth via estrogen receptor-independent mechanisms. Because catecholamines are also substrates for COMT, we hypothesize that catecholamines may abrogate the vasoprotective effects of estradiol by competing for COMT and inhibiting methoxyestradiol formation. To test this hypothesis, we investigated the antimitogenic/inhibitory effects of estradiol on human coronary artery SMC growth (cell number, DNA synthesis, collagen synthesis, and SMC migration) and ERK1/2 phosphorylation in the presence and absence of catecholamines. Norepinephrine, epinephrine, isoproterenol, and OR486 (COMT inhibitor) abrogated the inhibitory effects of estradiol on SMC growth and ERK1/2 phosphorylation. The interaction of catecholamines with estradiol was not affected by phentolamine or propanolol, α- and β-adrenoceptor antagonists, respectively. The antimitogenic effects of 2-hydroxyestradiol, but not 2-methoxyestradiol, were abrogated by epinephrine, isoproterenol, and OR486. Catecholamines inhibited the conversion of both estradiol and 2-hydroxyestradiol to 2-methoxyestradiol, and SMCs expressed CYP1A1 and CYP1B1. Our findings suggest that catecholamines within the coronary arteries may abrogate the antivasoocclusive effects of estradiol by blocking the conversion of catecholestradiols to methoxyestradiols. The interaction between catecholamines and estradiol metabolism may importantly define the cardiovascular effects of estradiol therapy in postmenopausal women.

Original languageEnglish
Pages (from-to)3922-3931
Number of pages10
JournalJournal of Clinical Endocrinology and Metabolism
Volume89
Issue number8
DOIs
Publication statusPublished - Aug 2004

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