17β-estradiol induces vasorelaxation by stimulating endothelial hydrogen sulfide release

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Abstract

Estrogen exerts vascular protective effects, but the underlying mechanisms remain to be understood fully. In recent years, hydrogen sulfide (H2S) has increasingly been recognized as an important signaling molecule in the cardiovascular system. Vascular H2S is produced from L-cysteine, catalyzed by cystathionine γ-lyase (CSE). In our study, apolipoprotein E (ApoE)-deficient mice were ovariectomized and implanted with placebo (OVX mice) or 17β-estradiol (E2) pellets (OVX + E2 mice). Compared with OVX mice, OVX + E2 mice showed increased plasma H2S levels (P = 0.012) and decreased aortic lesion area (P = 0.028). These effects were largely reversed when supplementing with the irreversible CSE inhibitor DL-propargylglycine (PPG) in the OVX + E2 + PPG mice. Meanwhile, the nitric oxide and prostacyclin-resistant responses to cumulative application of acetylcholine (ACh) were studied among all the three groups of femoral arteries. Compared with the arteries in the OVX group, the vasodilator sensitivity of arteries to ACh was increased in the OVX + E2 group and attenuated in the OVX + E2 + PPG group. E2 and estrogen receptor (ER) α agonist 4′,4″,4′″-(4-propyl-[1H]-pyrazole-1,3,5-triyl) trisphenol rapidly increased H2S release in human endothelial cells, but not partially selective ERβ agonist 2,3-bis-(4-hydroxyphenyl)-propionitrile. These effects were inhibited by ER antagonist ICI 182780 or by protein kinase G (PKG) inhibitor KT5823. Furthermore, endothelial PKG activity was increased by E2 (P = 0.003) and E2-induced vasodilation was inhibited by KT5823 (P = 0.009). In conclusion, the endothelial CSE/H2S pathway is activated by E2 through PKG, which leads to vasodilation. These actions may be relevant to estrogen's anti-atherogenic effect.

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