on February 7, 2008
Published online before print February 7, 2008, doi: 10.1161/HYPERTENSIONAHA.107.106575
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Submitted on November 29, 2007
From the Department of Obstetrics and Gynecology (R.K.D., B.I., M.R.), Clinic for Reproductive Endocrinology, University Hospital Zurich, Zurich, Switzerland; Zurich Center for Integrative Human Physiology (R.K.D.), University of Zurich, Zurich, Switzerland; Center for Clinical Pharmacology (R.K.D., E.K.J., D.G.G., L.C.Z.) and Departments of Medicine (R.K.D., E.K.J., D.G.G., L.C.Z.) and Pharmacology (E.K.J., L.C.Z.), University of Pittsburgh Medical Center, Pa; and the Inselspital (D.W.), Frauenheilkunde, University Hospital, Bern, Switzerland. * To whom correspondence should be addressed. E-mail: Raghvendra.dubey{at}usz.ch.
Abstract—Sequential conversion of estradiol (E) to 2/4-hydroxyestradiols and 2-/4-methoxyestradiols (MEs) by CYP450s and catechol-O-methyltransferase, respectively, contributes to the inhibitory effects of E on smooth muscle cells (SMCs) via estrogen receptor–independent mechanisms. Because medroxyprogesterone (MPA) is a substrate for CYP450s, we hypothesized that MPA may abrogate the inhibitory effects of E by competing for CYP450s and inhibiting the formation of 2/4-hydroxyestradiols and MEs. To test this hypothesis, we investigated the effects of E on SMC number, DNA and collagen synthesis, and migration in the presence and absence of MPA. The inhibitory effects of E on cell number, DNA synthesis, collagen synthesis, and SMC migration were significantly abrogated by MPA. For example, E (0.1µmol/L) reduced cell number to 51±3.6% of control, and this inhibitory effect was attenuated to 87.5±2.9% by MPA (10 nmol/L). Treatment with MPA alone did not alter any SMC parameters, and the abrogatory effects of MPA were not blocked by RU486 (progesterone-receptor antagonist), nor did treatment of SMCs with MPA influence the expression of estrogen receptor-
Revised on December 17, 2007
Medroxyprogesterone Abrogates the Inhibitory Effects of Estradiol on Vascular Smooth Muscle Cells by Preventing Estradiol Metabolism
Raghvendra K. Dubey*;
or estrogen receptor-
. In SMCs and microsomal preparations, MPA inhibited the sequential conversion of E to 2–2/4-hydroxyestradiol and 2-ME. Moreover, as compared with microsomes treated with E alone, 2-ME formation was inhibited when SMCs were incubated with microsomal extracts incubated with E plus MPA. Our findings suggest that the inhibitory actions of MPA on the metabolism of E to 2/4-hydroxyestradiols and MEs may negate the cardiovascular protective actions of estradiol in postmenopausal women receiving estradiol therapy combined with administration of MPA.
Key words: estradiol • progestins • cytochrome P450 • metabolism • cardiovascular disease • vascular remodeling
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