Epigenetic Regulation of the Nitric Oxide Pathway, 17-α Hydroxyprogesterone Caproate, and Recurrent Preterm Birth

Tracy A. Manuck; Lisa Smeester; Elizabeth M. Martin; Martha S. Tomlinson; Christina Smith; Michael W. Varner; Rebecca C. Fry

doi:10.1055/s-0037-1613682

American Journal of Perinatology, Inhaltsverzeichnis

Am J Perinatol 2018; 35(08): 721-728
DOI: 10.1055/s-0037-1613682

Original Article

Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Epigenetic Regulation of the Nitric Oxide Pathway, 17-α Hydroxyprogesterone Caproate, and Recurrent Preterm Birth

Tracy A. Manuck

¹Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina

,

Lisa Smeester

²Department of Environmental Sciences and Engineering, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina

,

Elizabeth M. Martin

²Department of Environmental Sciences and Engineering, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina

,

Martha S. Tomlinson

²Department of Environmental Sciences and Engineering, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina

,

Christina Smith

¹Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina

,

Michael W. Varner

³Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, University of Utah School of Medicine, Salt Lake City, Utah

⁴Intermountain Healthcare Women and Newborns Clinical Program, Salt Lake City, Utah

,

Rebecca C. Fry

²Department of Environmental Sciences and Engineering, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina

› Institutsangaben

Abstract

Objective We sought to evaluate nitric oxide pathway placental gene expression and the epigenome (CpG methylation) among women receiving 17-α hydroxyprogesterone caproate (17-OHPC) with and without recurrent preterm birth (PTB).

Study Design This was a case–control study. We prospectively recruited women with ≥ 1 prior singleton spontaneous PTB <34 weeks receiving 17-OHPC. DNA and RNA were isolated from placentas. RNA abundance (gene expression) and the methylome were analyzed for 84 genes in nitric oxide pathways. Women with recurrent PTB <34 weeks (cases) were compared with those delivering at term (controls). Statistical analysis included multivariable models with Bonferroni's corrected p-values.

Results In this study, 17 women met inclusion criteria; 7 preterm cases (delivered at 22.6 ± 2.9 weeks) and 10 term controls (delivered at 38.5 ± 0.8 weeks). Groups had similar PTB history, race/ethnicity, and socioeconomic risk factors for PTB. Twenty-seven nitric oxide genes displayed differential expression (p < 0.05 and q < 0.10) when comparing placentas from preterm cases and term controls; all were downregulated in preterm cases. Eight hundred sixty corresponding CpG sites were differentially methylated between the preterm cases and term controls (Bonferroni's p-value <0.05).

Conclusion CpG methylation and gene expression patterns in nitric oxide pathway genes differ among placentas from recurrent PTB compared with term birth following 17-OHPC exposure.

Keywords

17-α hydroxyprogesterone caproate - epigenetics - gene expression - nitric oxide - recurrent preterm birth

Volltext

Referenzen

References
1 Adams MM, Elam-Evans LD, Wilson HG, Gilbertz DA. Rates of and factors associated with recurrence of preterm delivery. JAMA 2000; 283 (12) 1591-1596
2 Meis PJ, Klebanoff M, Thom E. , et al; National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network. Prevention of recurrent preterm delivery by 17 alpha-hydroxyprogesterone caproate. N Engl J Med 2003; 348 (24) 2379-2385
3 Timofeev J, Singh J, Istwan N, Rhea D, Driggers RW. Spontaneous preterm birth in African-American and Caucasian women receiving 17α-hydroxyprogesterone caproate. Am J Perinatol 2014; 31 (01) 55-60
4 Manuck TA, Esplin MS, Biggio J. , et al; Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Genomics and Proteomics Network for Preterm Birth Research (GPN-PBR). Predictors of response to 17-alpha hydroxyprogesterone caproate for prevention of recurrent spontaneous preterm birth. Am J Obstet Gynecol 2016; 214 (03) 376.e1-376.e8
5 Manuck TA, Stoddard GJ, Fry RC, Esplin MS, Varner MW. Nonresponse to 17-alpha hydroxyprogesterone caproate for recurrent spontaneous preterm birth prevention: clinical prediction and generation of a risk scoring system. Am J Obstet Gynecol 2016; 215 (05) 622.e1-622.e8
6 Manuck TA, Watkins WS, Esplin MS. , et al; Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Genomics and Proteomics Network for Preterm Birth Research (GPN-PBR). Pharmacogenomics of 17-alpha hydroxyprogesterone caproate for recurrent preterm birth: a case-control study. BJOG 2017
7 Caritis SN, Venkataramanan R, Thom E. , et al; Eunice Kennedy Shriver National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network and Obstetric-Fetal Pharmacology Research Units Network. Relationship between 17-alpha hydroxyprogesterone caproate concentration and spontaneous preterm birth. Am J Obstet Gynecol 2014; 210 (02) 128.e1-128.e6
8 Manuck TA, Watkins WS, Moore B. , et al. Pharmacogenomics of 17-alpha hydroxyprogesterone caproate for recurrent preterm birth prevention. Am J Obstet Gynecol 2014; 210 (04) 321.e1-321.e21
9 Committee opinion no 611: method for estimating due date. Obstet Gynecol 2014; 124 (04) 863-866
10 Harris PA, Taylor R, Thielke R, Payne J, Gonzalez N, Conde JG. Research Electronic Data Capture (REDCap)--a metadata-driven methodology and workflow process for providing translational research informatics support. J Biomed Inform 2009; 42 (02) 377-381
11 Winn VD, Haimov-Kochman R, Paquet AC. , et al. Gene expression profiling of the human maternal-fetal interface reveals dramatic changes between midgestation and term. Endocrinology 2007; 148 (03) 1059-1079
12 Chwalisz K, Winterhager E, Thienel T, Garfield RE. Synergistic role of nitric oxide and progesterone during the establishment of pregnancy in the rat. Hum Reprod 1999; 14 (02) 542-552
13 Selles J, Polini N, Alvarez C, Massheimer V. Nongenomic action of progesterone in rat aorta: role of nitric oxide and prostaglandins. Cell Signal 2002; 14 (05) 431-436
14 Simoncini T, Mannella P, Fornari L. , et al. Differential signal transduction of progesterone and medroxyprogesterone acetate in human endothelial cells. Endocrinology 2004; 145 (12) 5745-5756
15 Simoncini T, Caruso A, Garibaldi S. , et al. Activation of nitric oxide synthesis in human endothelial cells using nomegestrol acetate. Obstet Gynecol 2006; 108 (04) 969-978
16 Pang Y, Dong J, Thomas P. Progesterone increases nitric oxide synthesis in human vascular endothelial cells through activation of membrane progesterone receptor-α. Am J Physiol Endocrinol Metab 2015; 308 (10) E899-E911
17 Sladek SM, Magness RR, Conrad KP. Nitric oxide and pregnancy. Am J Physiol 1997; 272 (2 Pt 2): R441-R463
18 Buxton IL, Milton D, Barnett SD, Tichenor SD. Agonist-specific compartmentation of cGMP action in myometrium. J Pharmacol Exp Ther 2010; 335 (01) 256-263
19 Chen Z, Yuhanna IS, Galcheva-Gargova Z, Karas RH, Mendelsohn ME, Shaul PW. Estrogen receptor alpha mediates the nongenomic activation of endothelial nitric oxide synthase by estrogen. J Clin Invest 1999; 103 (03) 401-406
20 MacRitchie AN, Jun SS, Chen Z. , et al. Estrogen upregulates endothelial nitric oxide synthase gene expression in fetal pulmonary artery endothelium. Circ Res 1997; 81 (03) 355-362
21 Ricciardolo FL, Nijkamp FP, Folkerts G. Nitric oxide synthase (NOS) as therapeutic target for asthma and chronic obstructive pulmonary disease. Curr Drug Targets 2006; 7 (06) 721-735
22 Catov JM, Scifres CM, Caritis SN, Bertolet M, Larkin J, Parks WT. Neonatal outcomes following preterm birth classified according to placental features. Am J Obstet Gynecol 2017; 216 (04) 411.e1-411.e14
23 Morgan TK. Role of the placenta in preterm birth: a review. Am J Perinatol 2016; 33 (03) 258-266
24 Izumi H, Garfield RE. Relaxant effects of nitric oxide and cyclic GMP on pregnant rat uterine longitudinal smooth muscle. Eur J Obstet Gynecol Reprod Biol 1995; 60 (02) 171-180
25 Izumi H, Yallampalli C, Garfield RE. Gestational changes in L-arginine-induced relaxation of pregnant rat and human myometrial smooth muscle. Am J Obstet Gynecol 1993; 169 (05) 1327-1337
26 Yallampalli C, Izumi H, Byam-Smith M, Garfield RE. An L-arginine-nitric oxide-cyclic guanosine monophosphate system exists in the uterus and inhibits contractility during pregnancy. Am J Obstet Gynecol 1994; 170 (1 Pt 1): 175-185
27 Vora NL, Smeester L, Boggess K, Fry RC. Investigating the role of fetal gene expression in preterm birth. Reprod Sci 2017; 24 (06) 824-828
28 Lysell J, Stjernholm Vladic Y, Ciarlo N, Holmgren A, Sahlin L. Immunohistochemical determination of thioredoxin and glutaredoxin distribution in the human cervix, and possible relation to cervical ripening. Gynecol Endocrinol 2003; 17 (04) 303-310
29 Sahlin L, Wang H, Stjernholm Y. , et al. The expression of glutaredoxin is increased in the human cervix in term pregnancy and immediately post-partum, particularly after prostaglandin-induced delivery. Mol Hum Reprod 2000; 6 (12) 1147-1153
30 Hirota Y, Acar N, Tranguch S. , et al. Uterine FK506-binding protein 52 (FKBP52)-peroxiredoxin-6 (PRDX6) signaling protects pregnancy from overt oxidative stress. Proc Natl Acad Sci U S A 2010; 107 (35) 15577-15582
31 Li L, Shoji W, Oshima H, Obinata M, Fukumoto M, Kanno N. Crucial role of peroxiredoxin III in placental antioxidant defense of mice. FEBS Lett 2008; 582 (16) 2431-2434
32 Hannan NJ, Beard S, Binder NK. , et al. Key players of the necroptosis pathway RIPK1 and SIRT2 are altered in placenta from preeclampsia and fetal growth restriction. Placenta 2017; 51: 1-9
33 Fajardy I, Moitrot E, Vambergue A, Vandersippe-Millot M, Deruelle P, Rousseaux J. Time course analysis of RNA stability in human placenta. BMC Mol Biol 2009; 10: 21
34 Caritis SN, Sharma S, Venkataramanan R. , et al; Eunice Kennedy Shriver National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network. Pharmacokinetics of 17-hydroxyprogesterone caproate in multifetal gestation. Am J Obstet Gynecol 2011; 205 (01) 40.e1-40.e8