title: 17β-estradiol induces vasorelaxation by stimulating endothelial hydrogen sulfide release.
abstract: Estrogen exerts vascular protective effects, but the underlying mechanisms remain to be understood fully. In recent years, hydrogen sulfide (H(2)S) has increasingly been recognized as an important signaling molecule in the cardiovascular system. Vascular H(2)S 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 (E(2)) pellets (OVX + E(2) mice). Compared with OVX mice, OVX + E(2) mice showed increased plasma H(2)S 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 + E(2) + 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 + E(2) group and attenuated in the OVX + E(2) + PPG group. E(2) and estrogen receptor (ER) α agonist 4',4″,4'″-(4-propyl-[1H]-pyrazole-1,3,5-triyl) trisphenol rapidly increased H(2)S 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 E(2) (P = 0.003) and E(2)-induced vasodilation was inhibited by KT5823 (P = 0.009). In conclusion, the endothelial CSE/H(2)S pathway is activated by E(2) through PKG, which leads to vasodilation. These actions may be relevant to estrogen's anti-atherogenic effect.
authors.affiliation: Department of Physiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong Province, China.
authors.forename: Kewen
authors.initials: K
authors.lastname: Zhou
authors.forename: Qi
authors.initials: Q
authors.lastname: Gao
authors.forename: Shuhui
authors.initials: S
authors.lastname: Zheng
authors.forename: Sinian
authors.initials: S
authors.lastname: Pan
authors.forename: Ping
authors.initials: P
authors.lastname: Li
authors.forename: Kun
authors.initials: K
authors.lastname: Suo
authors.forename: Tommaso
authors.initials: T
authors.lastname: Simoncini
authors.forename: Tinghuai
authors.initials: T
authors.lastname: Wang
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Fu
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000480:Alkynes / Q000494:pharmacology; D000818:Animals; D001011:Aorta / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control; D017869:Cyclic GMP-Dependent Protein Kinases / Q000235:genetics* / Q000378:metabolism; D003542:Cystathionine gamma-Lyase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D003692:Delayed-Action Preparations / Q000494:pharmacology*; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D004958:Estradiol / Q000494:pharmacology*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D005998:Glycine / Q000031:analogs & derivatives / Q000494:pharmacology; D006862:Hydrogen Sulfide / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D010052:Ovariectomy; D058226:Plaque, Atherosclerotic / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011960:Receptors, Estrogen / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects*
chemical_list: D000480:Alkynes; D001057:Apolipoproteins E; D003692:Delayed-Action Preparations; D047428:Protein Kinase Inhibitors; D011960:Receptors, Estrogen; D004958:Estradiol; C009055:propargylglycine; D017869:Cyclic GMP-Dependent Protein Kinases; D003542:Cystathionine gamma-Lyase; D000109:Acetylcholine; D005998:Glycine; D006862:Hydrogen Sulfide