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

Estrogen exerts vascular protective effects, but the underlyingmechanisms remain to be understood fully. In recent years, hydrogen sulfide (H2S) has increasingly been recognized as an important signalingmolecule in the cardiovascular system.VascularH2S is produced from L-cysteine, catalyzed by cystathionine g-lyase (CSE). In our study, apolipoprotein E (ApoE)-deficient mice were ovariectomized and implanted with placebo (OVXmice) or 17b-estradiol (E2) pellets (OVX + E2mice). ComparedwithOVXmice,OVX + E2mice showed increased plasma H2S levels (P 1⁄4 0.012) and decreased aortic lesion area (P 1⁄4 0.028). These effects were largely reversed when supplementing with the irreversible CSE inhibitor DL-propargylglycine (PPG) in theOVX + E2 + PPGmice. 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 AChwas increased in theOVX + E2 group and attenuated in theOVX + E2 + PPG group. E2 and estrogen receptor (ER) a 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 ERb 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 1⁄4 0.003) and E2induced vasodilation was inhibited by KT5823 (P 1⁄4 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.