Estrogen replacement therapy in ovariectomized nonpregnant ewes stimulates uterine artery hydrogen sulfide biosynthesis by selectively up-regulating cystathionine β-synthase expression

Thomas J. Lechuga, Hong Hai Zhang, Lili Sheibani, Muntarin Karim, Jason Jia, Ronald R. Magness, Charles R. Rosenfeld, Dong Bao Chen

Research output: Contribution to journalArticle

20 Scopus citations


Estrogens dramatically dilate numerous vascular beds with the greatest response in the uterus. Endogenous hydrogen sulfide (H<inf>2</inf>S) is a potent vasodilator and proangiogenic second messenger, which is synthesized from L-cysteine by cystathionine β-synthase (CBS) and cystathionine γ-lyase (CSE). We hypothesized that estrogen replacement therapy (ERT) selectively stimulates H<inf>2</inf>S biosynthesis in uterine artery (UA) and other systemic arteries. Intact and endothelium-denuded UA, mesenteric artery (MA), and carotid artery (CA) were obtained from ovariectomized nonpregnant ewes (n = 5/group) receiving vehicle or estradiol-17β replacement therapy (ERT). Total RNA and protein were extracted for measuring CBS and CSE, and H<inf>2</inf>S production was determined by the methylene blue assay. Paraffin-embedded UA rings were used to localize CBS and CSE proteins by immunofluorescence microscopy. ERT significantly stimulated CBS mRNA and protein without altering CSE mRNA or protein in intact and denuded UA. Quantitative immunofluorescence microscopic analyses showed CBS and CSE protein localization in endothelium and smooth muscle and confirmed that ERT stimulated CBS but not CSE protein expression in UA endothelium and smooth muscle. ERT also stimulated CBS, but not CSE, mRNA and protein expression in intact and denuded MA but not CA in ovariectomized ewes. Concomitantly, ERT stimulated UA and MA but not CA H<inf>2</inf>S production. ERT-stimulated UA H<inf>2</inf>S production was completely blocked by a specific CBS but not CSE inhibitor. Thus, ERT selectively stimulates UA and MA but not CA H<inf>2</inf>S biosynthesis by specifically up-regulating CBS expression, implicating a role of H<inf>2</inf>S in estrogen-induced vasodilation and postmenopausal women's health.

Original languageEnglish (US)
Pages (from-to)2288-2298
Number of pages11
Issue number6
StatePublished - Jun 1 2015


ASJC Scopus subject areas

  • Endocrinology

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