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

Raghvendra K. Dubey, Edwin K. Jackson, Delbert G. Gillespie, Lefteris C. Zacharia, Dorothea Wunder, Bruno Imthurn, Marinella Rosselli

Research output: Contribution to journalArticle

9 Citations (Scopus)

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-α or estrogen receptor-β. 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.

Original languageEnglish
Pages (from-to)1197-1202
Number of pages6
JournalHypertension
Volume51
Issue number4 PART 2 SUPPL.
DOIs
Publication statusPublished - Apr 2008

Keywords

  • Cardiovascular disease
  • Cytochrome P450
  • Estradiol
  • Metabolism
  • Progestins
  • Vascular remodeling

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