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
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 20:12
Dernière modification de la notice
20/08/2019 17:02