Endogenous hydrogen sulfide (H₂S) is a potent vasodilator and proangiogenic second messenger synthesized from L-cysteine by cystathionine β-synthase (CBS) and cystathionine γ -lyase (CTH). Estrogens are potent vasodilators that stimulate H₂S biosynthesis in uterine arteries (UA) in vivo; however, the underlying mechanisms are unknown. We hypothesized that estrogens stimulate H₂S biosynthesis in UA endothelial cells (UAEC) via specific estrogen receptor (ER)-dependent mechanisms. In cultured primary UAEC, treatment with estradiol-17β (E₂β) stimulated CBS and CTH mRNAs and proteins in a time- and concentration-dependent fashion. As little as 0.1 nM E₂β was effective in increasing CBS and CTH expressions and these stimulatory effects maximized with 10–100 nM E₂β at 48–72 h. E₂β also activated CBS and CTH promoters in UAEC, leading to CBS and CTH expression. Treatment with E₂β stimulated H₂S production, which was blocked by specific inhibitors of either CBS or CTH and their combination and the ER antagonist ICI 182780. Treatment with either specific agonist of ERα or ERβ stimulated both CBS and CTH mRNA and protein expressions and H₂S production to levels similar to that of E₂β. Specific antagonist of either ERα or ERβ blocked E₂β-stimulated CBS and CTH mRNA and protein expressions and H₂S production. Combinations of either ERα or ERβ agonists or their antagonists had no additive effects. Thus, E₂β stimulates H₂S production by upregulating CBS and CTH mRNA and protein expressions through specific ERα or ERβ-dependent CBS and CTH transcription in UAEC in vitro.

Summary Sentence

Estradiol-17β stimulates uterine artery endothelial cell hydrogen sulfide biosynthesis.