Medroxyprogesterone abrogates the inhibitory effects of estradiol on vascular smooth muscle cells by preventing estradiol metabolism.

Détails

ID Serval
serval:BIB_DD5FDCA946F0
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Institution
Titre
Medroxyprogesterone abrogates the inhibitory effects of estradiol on vascular smooth muscle cells by preventing estradiol metabolism.
Périodique
Hypertension
Auteur(s)
Dubey R.K., Jackson E.K., Gillespie D.G., Zacharia L.C., Wunder D., Imthurn B., Rosselli M.
ISSN
1524-4563
Statut éditorial
Publié
Date de publication
2008
Peer-reviewed
Oui
Volume
51
Numéro
4
Pages
1197-1202
Langue
anglais
Notes
Publication types: Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
Résumé
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 (0.1micromol/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-alpha or estrogen receptor-beta. 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.
Mots-clé
Aorta, Cell Movement, Cells, Cultured, Contraceptives, Oral, Synthetic, Cytochrome P-450 Enzyme System, Drug Interactions, Estradiol, Estrogen Receptor alpha, Estrogen Receptor beta, Estrogens, Female, Humans, Medroxyprogesterone, Microsomes, Muscle, Smooth, Vascular, Myocytes, Smooth Muscle, Platelet-Derived Growth Factor
Pubmed
Web of science
Open Access
Oui
Création de la notice
04/03/2009 19:12
Dernière modification de la notice
20/08/2019 16:02
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