title: Estrogen Replacement Therapy in Ovariectomized Nonpregnant Ewes Stimulates Uterine Artery Hydrogen Sulfide Biosynthesis by Selectively Up-Regulating Cystathionine β-Synthase Expression.
abstract: Estrogens dramatically dilate numerous vascular beds with the greatest response in the uterus. Endogenous hydrogen sulfide (H2S) 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 H2S 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 H2S 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 H2S production. ERT-stimulated UA H2S production was completely blocked by a specific CBS but not CSE inhibitor. Thus, ERT selectively stimulates UA and MA but not CA H2S biosynthesis by specifically up-regulating CBS expression, implicating a role of H2S in estrogen-induced vasodilation and postmenopausal women's health.
authors.affiliation: Departments of Obstetrics and Gynecology (T.J.L., H.H.Z., L.S., M.K., J.J., D.-b.C.) and Pathology (T.J.L., D.-b.C.), University of California Irvine, Irvine, California 92697; Department of Obstetrics and Gynecology, Pediatrics, and Animal Sciences (R.R.M.), University of Wisconsin-Madison, Madison, Wisconsin 53715; and Division of Neonatal-Perinatal Medicine (C.R.R.), Department of Pediatrics and Obstetrics and Gynecology, University of Texas Southwestern Medical Center, Dallas, Texas 75390.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Lechuga
authors.forename: Hong-hai
authors.initials: HH
authors.lastname: Zhang
authors.forename: Lili
authors.initials: L
authors.lastname: Sheibani
authors.forename: Muntarin
authors.initials: M
authors.lastname: Karim
authors.forename: Jason
authors.initials: J
authors.lastname: Jia
authors.forename: Ronald R
authors.initials: RR
authors.lastname: Magness
authors.forename: Charles R
authors.initials: CR
authors.lastname: Rosenfeld
authors.forename: Dong-bao
authors.initials: DB
authors.lastname: Chen
mesh_terms: D000818:Animals; D002339:Carotid Arteries / Q000187:drug effects / Q000378:metabolism; D003541:Cystathionine beta-Synthase / Q000235:genetics / Q000378:metabolism*; D004958:Estradiol / Q000494:pharmacology; D015914:Estrogen Replacement Therapy; D005260:Female; D006862:Hydrogen Sulfide / Q000378:metabolism*; D008856:Microscopy, Fluorescence; D010052:Ovariectomy; D012756:Sheep; D055988:Uterine Artery / Q000378:metabolism*
chemical_list: D004958:Estradiol; D003541:Cystathionine beta-Synthase; D006862:Hydrogen Sulfide
references.citation: Am J Physiol. 1998 Nov;275(5 Pt 2):H1845-56
references.pmid: 9815093
references.citation: Am J Physiol Regul Integr Comp Physiol. 2002 Jul;283(1):R29-45
references.pmid: 12069928
references.citation: N Engl J Med. 1999 Jun 10;340(23):1801-11
references.pmid: 10362825
references.citation: J Biol Chem. 2004 Nov 19;279(47):49199-205
references.pmid: 15347670
references.citation: J Biol Chem. 2005 Jan 7;280(1):347-54
references.pmid: 15509581
references.citation: Biol Reprod. 2005 Mar;72(3):530-7
references.pmid: 15564597
references.citation: J Physiol. 2005 May 15;565(Pt 1):71-83
references.pmid: 15774510
references.citation: J Physiol. 2005 May 15;565(Pt 1):85-99
references.pmid: 15774511
references.citation: Biol Reprod. 2006 May;74(5):832-8
references.pmid: 16436525
references.citation: Cardiovasc Res. 2007 Oct 1;76(1):29-40
references.pmid: 17631873
references.citation: Nat Rev Drug Discov. 2007 Nov;6(11):917-35
references.pmid: 17948022
references.citation: Am J Physiol Heart Circ Physiol. 2007 Dec;293(6):H3713-9
references.pmid: 17951367
references.citation: J Soc Gynecol Investig. 2003 May;10(4):205-15
references.pmid: 12759149
references.citation: Eur J Obstet Gynecol Reprod Biol. 2003 Sep 22;110 Suppl 1:S55-61
references.pmid: 12965091
references.citation: Endocrinology. 2004 Jan;145(1):113-25
references.pmid: 14512434
references.citation: Biol Reprod. 2004 Jun;70(6):1886-94
references.pmid: 14985241
references.citation: Am J Physiol Heart Circ Physiol. 2004 Nov;287(5):H2316-23
references.pmid: 15191893
references.citation: Pediatr Res. 1973 Mar;7(3):139-48
references.pmid: 4690359
references.citation: Am J Obstet Gynecol. 1973 Apr 15;115(8):1045-52
references.pmid: 4734886
references.citation: Am J Physiol. 1977 Mar;232(3):H231-5
references.pmid: 842676
references.citation: Am J Obstet Gynecol. 1985 Oct 15;153(4):417-25
references.pmid: 4050915
references.citation: Am J Physiol. 1989 Apr;256(4 Pt 1):E536-42
references.pmid: 2650565
references.citation: Am J Physiol. 1991 Mar;260(3 Pt 1):E464-70
references.pmid: 2003600
references.citation: Am J Obstet Gynecol. 1992 Sep;167(3):828-33
references.pmid: 1530046
references.citation: Am J Physiol. 1993 Nov;265(5 Pt 1):E690-8
references.pmid: 8238494
references.citation: Proc Natl Acad Sci U S A. 1994 May 24;91(11):5212-6
references.pmid: 7515189
references.citation: J Clin Pharmacol. 1995 Mar;35(3):314-29
references.pmid: 7608324
references.citation: J Neurosci. 1996 Feb 1;16(3):1066-71
references.pmid: 8558235
references.citation: J Clin Invest. 1996 Nov 1;98(9):2158-66
references.pmid: 8903336
references.citation: Arch Biochem Biophys. 1998 Feb 1;350(1):95-103
references.pmid: 9466825
references.citation: J Pharm Pharmacol. 1998 May;50(5):531-8
references.pmid: 9643447
references.citation: Hum Reprod. 1998 May;13(5):1361-7
references.pmid: 9647573
references.citation: Am J Physiol. 1998 Sep;275(3 Pt 2):H731-43
references.pmid: 9724274
references.citation: Genomics. 1998 Sep 15;52(3):312-24
references.pmid: 9790750
references.citation: J Endocrinol. 2012 Oct;215(1):97-106
references.pmid: 22798015
references.citation: Endocrinology. 2012 Dec;153(12):6012-20
references.pmid: 23070547
references.citation: Hypertension. 2013 Feb;61(2):480-7
references.pmid: 23319542
references.citation: Bull Exp Biol Med. 2012 Nov;154(1):104-7
references.pmid: 23330102
references.citation: Mol Hum Reprod. 2013 Mar;19(3):169-76
references.pmid: 23041593
references.citation: Biochem Biophys Res Commun. 2013 Apr 19;433(4):519-25
references.pmid: 23524260
references.citation: Horm Behav. 1998 Oct;34(2):171-82
references.pmid: 9799627
references.citation: J Pharmacol Exp Ther. 2008 Feb;324(2):876-82
references.pmid: 18029544
references.citation: Science. 2008 Oct 24;322(5901):587-90
references.pmid: 18948540
references.citation: Sci Signal. 2009;2(68):re2
references.pmid: 19401594
references.citation: Hypertension. 2009 Aug;54(2):352-8
references.pmid: 19528364
references.citation: Adv Ther. 2009 Aug;26(8):805-11
references.pmid: 19672567
references.citation: Proc Natl Acad Sci U S A. 2009 Dec 22;106(51):21972-7
references.pmid: 19955410
references.citation: Am J Physiol Heart Circ Physiol. 2011 Feb;300(2):H440-7
references.pmid: 21131483
references.citation: J Biol Chem. 2011 Jul 29;286(30):26450-60
references.pmid: 21659522
references.citation: Pharmacology. 2011;88(1-2):55-64
references.pmid: 21791946
references.citation: Fertil Steril. 2011 Dec;96(6):1445-50
references.pmid: 21982290
references.citation: PLoS One. 2012;7(8):e41614
references.pmid: 22870237
references.citation: Am J Physiol Heart Circ Physiol. 2013 Jun 1;304(11):H1446-54
references.pmid: 23525712
references.citation: Menopause. 2013 Oct;20(10):1084-91
references.pmid: 23571523
references.citation: World J Gastroenterol. 2013 Oct 28;19(40):6863-8
references.pmid: 24187462
references.citation: Microcirculation. 2014 Jan;21(1):38-47
references.pmid: 23941526
references.citation: Prostaglandins Other Lipid Mediat. 2000 Mar;60(4-6):103-18
references.pmid: 10751641
references.citation: Hypertension. 2000 Dec;36(6):970-4
references.pmid: 11116109
references.citation: Am J Physiol Heart Circ Physiol. 2001 Apr;280(4):H1699-705
references.pmid: 11247782
references.citation: EMBO J. 2001 Nov 1;20(21):6008-16
references.pmid: 11689441
references.citation: Cardiovasc Res. 1999 Jan;41(1):307-11
references.pmid: 10325979