Elevated Testosterone Reduces Uterine Blood Flow, Spiral Artery Elongation, and Placental Oxygenation in Pregnant Rats

Hypertension

Volumn 67, Issue 3, 2016, Pages 630-639

  Gopalakrishnan, Kathirvel ^a   Mishra, Jay S ^a   Chinnathambi, Vijayakumar ^a   Vincent, Kathleen L ^a,b   Patrikeev, Igor ^b   Motamedi, Massoud ^b   Saade, George R ^a   Hankins, Gary D ^a   Sathishkumar, Kunju ^a  

^a University of Texas Medical Branch School of Medicine   (United States)

^b UNIVERSITY OF TEXAS MEDICAL BRANCH   (United States)

Author keywords

hypoxia; placenta; preeclampsia; testosterone; vascular resistance

Indexed keywords

HYPOXIA INDUCIBLE FACTOR 1ALPHA; PIMONIDAZOLE; TESTOSTERONE; TESTOSTERONE PROPIONATE;

ANGIOGENESIS; ANIMAL EXPERIMENT; ANIMAL MODEL; ARTERY DIAMETER; ARTERY LENGTH; ARTICLE; BLOOD OXYGENATION; BLOOD VESSEL PARAMETERS; CONTROLLED STUDY; ECHOGRAPHY; FEMALE; FETOPLACENTAL HYPOXIA; FETUS CIRCULATION; FETUS HYPOXIA; FETUS WEIGHT; GENE EXPRESSION; GESTATIONAL AGE; INTRAUTERINE GROWTH RETARDATION; MALE; MICRO-COMPUTED TOMOGRAPHY; NONHUMAN; OXYGENATION; PLACENTA CIRCULATION; PLACENTA FUNCTION; PLACENTA WEIGHT; PLACENTAL OXYGENATION; PREGNANCY; PRIORITY JOURNAL; RADIAL ARTERY; RAT; SEX DETERMINATION; SPIRAL ARTERY ELONGATION; SPRAGUE DAWLEY RAT; TESTOSTERONE BLOOD LEVEL; UMBILICAL ARTERY; UTERUS BLOOD FLOW; VASCULARIZATION; X RAY ANALYSIS; ANIMAL; BLOOD; BLOOD FLOW VELOCITY; BREEDING; FETAL GROWTH RETARDATION; METABOLISM; OXYGEN CONSUMPTION; PATHOPHYSIOLOGY; PHYSIOLOGY; PLACENTA; UTERINE ARTERY; UTERUS;

ANIMALS; BLOOD FLOW VELOCITY; FEMALE; FETAL GROWTH RETARDATION; MALE; OXYGEN CONSUMPTION; PLACENTA; PREGNANCY; PREGNANCY, ANIMAL; RATS; RATS, SPRAGUE-DAWLEY; TESTOSTERONE; UTERINE ARTERY; UTERUS; X-RAY MICROTOMOGRAPHY;

EID: 84958045988     PISSN: 0194911X     EISSN: 15244563     Source Type: Journal    
DOI: 10.1161/HYPERTENSIONAHA.115.06946     Document Type: Article

References (77)

1. Martin JA, Hamilton BE, Sutton PD, Ventura SJ, Menacker F, Munson ML. Births: final data for 2003. Natl Vital Stat Rep. 2005; 54: 1-116.
2. Manning FA. Intrauterine growth retardation: etiology, pathophysiology, diagnosis, and treatment. Fetal Medicine: Principles and Practice. Norwalk, Connecticut: Appleton & Lange; 1995.
3. Barker DJ. Fetal origins of coronary heart disease. BMJ. 1995; 311: 171-174.
4. Gluckman PD, Hanson MA, Pinal C. The developmental origins of adult disease. Matern Child Nutr. 2005; 1: 130-141. doi: 10.1111/j.1740-8709.2005.00020.x.
5. Ong KK, Dunger DB. Perinatal growth failure: the road to obesity, insulin resistance and cardiovascular disease in adults. Best Pract Res Clin Endocrinol Metab. 2002; 16: 191-207. doi: 10.1053/beem.2002.0195.
6. Szymanowski K, Chmaj-Wierzchowska K, Florek E, Opala T. [Influence of tobacco smoking to development of the fetus, newborn and child-a review]. Przegl Lek. 2006; 63: 1135-1137.
7. Zhang X, Sliwowska JH, Weinberg J. Prenatal alcohol exposure and fetal programming: effects on neuroendocrine and immune function. Exp Biol Med (Maywood). 2005; 230: 376-388.
8. Kajantie E. Fetal origins of stress-related adult disease. Ann N Y Acad Sci. 2006; 1083: 11-27. doi: 10.1196/annals.1367.026.
9. Steckler TL, Roberts EK, Doop DD, Lee TM, Padmanabhan V. Developmental programming in sheep: administration of testosterone during 60-90 days of pregnancy reduces breeding success and pregnancy outcome. Theriogenology. 2007; 67: 459-467. doi: 10.1016/j. theriogenology.2006.08.010.
10. Vandenbosche RC, Kirchner JT. Intrauterine growth retardation. Am Fam Physician. 1998; 58: 1384-1390, 1393.
11. Thaler I, Manor D, Itskovitz J, Rottem S, Levit N, Timor-Tritsch I, Brandes JM. Changes in uterine blood flow during human pregnancy. Am J Obstet Gynecol. 1990; 162: 121-125.
12. Magness R. Maternal cardiovascular and other physiologic responses to the endocrinology of pregnancy. In: Bazer FW, ed. The Endocrinology of Pregnancy. Totowa: Humana Press Inc; 1998: 507-539.
13. Osol G, Mandala M. Maternal uterine vascular remodeling during pregnancy. Physiology (Bethesda). 2009; 24: 58-71. doi: 10.1152/physiol.00033.2008.
14. Croy BA, Yamada A, DeMayo FJ, Adamson SL. The Guide to Investigation of Mouse Pregnancy. 1st ed. London, UK: Academic Press (Elsevier); 2014.
15. Carlsen SM, Jacobsen G, Romundstad P. Maternal testosterone levels during pregnancy are associated with offspring size at birth. Eur J Endocrinol. 2006; 155: 365-370. doi: 10.1530/eje.1.02200.
16. Voegtline KM, Costigan KA, Kivlighan KT, Henderson JL, DiPietro JA. Sex-specific associations of maternal prenatal testosterone levels with birth weight and weight gain in infancy. J Dev Orig Health Dis. 2013; 4: 280-284. doi: 10.1017/S2040174413000135.
17. Salamalekis E, Bakas P, Vitoratos N, Eleptheriadis M, Creatsas G. Androgen levels in the third trimester of pregnancy in patients with preeclampsia. Eur J Obstet Gynecol Reprod Biol. 2006; 126: 16-19. doi: 10.1016/j.ejogrb.2005.07.007.
18. Acromite MT, Mantzoros CS, Leach RE, Hurwitz J, Dorey LG. Androgens in preeclampsia. Am J Obstet Gynecol. 1999; 180(1 pt 1): 60-63.
19. Ghorashi V, Sheikhvatan M. The relationship between serum concentration of free testosterone and pre-eclampsia. Endokrynol Pol. 2008; 59: 390-392.
20. Carlsen SM, Romundstad P, Jacobsen G. Early second-trimester maternal hyperandrogenemia and subsequent preeclampsia: a prospective study. Acta Obstet Gynecol Scand. 2005; 84: 117-121. doi: 10.1111/j.0001-6349.2005.00493.x.
21. Troisi R, Potischman N, Roberts JM, Ness R, Crombleholme W, Lykins D, Siiteri P, Hoover RN. Maternal serum oestrogen and androgen concentrations in preeclamptic and uncomplicated pregnancies. Int J Epidemiol. 2003; 32: 455-460.
22. Sir-Petermann T, Maliqueo M, Angel B, Lara HE, Pérez-Bravo F, Recabarren SE. Maternal serum androgens in pregnant women with polycystic ovarian syndrome: possible implications in prenatal androgenization. Hum Reprod. 2002; 17: 2573-2579.
23. Mains LM, Lathi RB, Burney RO, Dahan MH. Serum total testosterone levels in a patient with late onset 21-hydroxylase deficiency and a twin gestation. Fertil Steril. 2007; 87: 1212.e5-1212.e8. doi: 10.1016/j. fertnstert.2006.07.1545.
24. Spiro RP, Christian SL, Ledbetter DH, New MI, Wilson RC, Roizen N, Rosenfield RL. Intrauterine growth retardation associated with maternal uniparental disomy for chromosome 6 unmasked by congenital adrenal hyperplasia. Pediatr Res. 1999; 46: 510-513. doi: 10.1203/00006450-199911000-00004.
25. Smith LM, Cloak CC, Poland RE, Torday J, Ross MG. Prenatal nicotine increases testosterone levels in the fetus and female offspring. Nicotine Tob Res. 2003; 5: 369-374.
26. Kandel DB, Udry JR. Prenatal effects of maternal smoking on daughters' smoking: nicotine or testosterone exposure? Am J Public Health. 1999; 89: 1377-1383.
27. Rizwan S, Manning JT, Brabin BJ. Maternal smoking during pregnancy and possible effects of in utero testosterone: evidence from the 2D: 4D finger length ratio. Early Hum Dev. 2007; 83: 87-90. doi: 10.1016/j. earlhumdev.2006.05.005.
28. Rohrmann S, Sutcliffe CG, Bienstock JL, Monsegue D, Akereyeni F, Bradwin G, Rifai N, Pollak MN, Agurs-Collins T, Platz EA. Racial variation in sex steroid hormones and the insulin-like growth factor axis in umbilical cord blood of male neonates. Cancer Epidemiol Biomarkers Prev. 2009; 18: 1484-1491. doi: 10.1158/1055-9965. EPI-08-0817.
29. Agurs-Collins T, Rohrmann S, Sutcliffe C, Bienstock JL, Monsegue D, Akereyeni F, Bradwin G, Rifai N, Pollak MN, Platz EA. Racial variation in umbilical cord blood sex steroid hormones and the insulin- like growth factor axis in African-American and white female neonates. Cancer Causes Control. 2012; 23: 445-454. doi: 10.1007/s10552-011-9893-6.
30. Potischman N, Troisi R, Thadhani R, Hoover RN, Dodd K, Davis WW, Sluss PM, Hsieh CC, Ballard-Barbash R. Pregnancy hormone concentrations across ethnic groups: implications for later cancer risk. Cancer Epidemiol Biomarkers Prev. 2005; 14: 1514-1520. doi: 10.1158/1055- 9965.EPI-04-0869.
31. Chinnathambi V, Balakrishnan M, Ramadoss J, Yallampalli C, Sathishkumar K. Testosterone alters maternal vascular adaptations: role of the endothelial NO system. Hypertension. 2013; 61: 647-654. doi: 10.1161/HYPERTENSIONAHA.111.00486.
32. Sathishkumar K, Elkins R, Chinnathambi V, Gao H, Hankins GD, Yallampalli C. Prenatal testosterone-induced fetal growth restriction is associated with down-regulation of rat placental amino acid transport. Reprod Biol Endocrinol. 2011; 9: 110. doi: 10.1186/1477-7827-9-110.
33. Chinnathambi V, Balakrishnan M, Yallampalli C, Sathishkumar K. Prenatal testosterone exposure leads to hypertension that is gonadal hormone-dependent in adult rat male and female offspring. Biol Reprod. 2012; 206: 507.e1-507.e10.
34. Chinnathambi V, Yallampalli C, Sathishkumar K. Prenatal testosterone induces sex-specific dysfunction in endothelium-dependent relaxation pathways in adult male and female rats. Biol Reprod. 2013; 89: 97. doi: 10.1095/biolreprod.113.111542.
35. Dean A, Smith LB, Macpherson S, Sharpe RM. The effect of dihydrotestosterone exposure during or prior to the masculinization programming window on reproductive development in male and female rats. Int J Androl. 2012; 35: 330-339. doi: 10.1111/j.1365-2605.2011.01236.x.
36. Dean A, Sharpe RM. Clinical review: anogenital distance or digit length ratio as measures of fetal androgen exposure: relationship to male reproductive development and its disorders. J Clin Endocrinol Metab. 2013; 98: 2230-2238. doi: 10.1210/jc.2012-4057.
37. Lombardo MV, Ashwin E, Auyeung B, Chakrabarti B, Taylor K, Hackett G, Bullmore ET, Baron-Cohen S. Fetal testosterone influences sexually dimorphic gray matter in the human brain. J Neurosci. 2012; 32: 674-680. doi: 10.1523/JNEUROSCI.4389-11.2012.
38. Morisset AS, Dubé MC, Drolet R, Pelletier M, Labrie F, Luu- The V, Tremblay Y, Robitaille J, John Weisnagel S, Tchernof A. Androgens in the maternal and fetal circulation: association with insulin resistance. J Matern Fetal Neonatal Med. 2013; 26: 513-519. doi: 10.3109/14767058.2012.735725.
39. Rae M, Grace C, Hogg K, Wilson LM, McHaffie SL, Ramaswamy S, MacCallum J, Connolly F, McNeilly AS, Duncan C. The pancreas is altered by in utero androgen exposure: implications for clinical conditions such as polycystic ovary syndrome (PCOS). PLoS One. 2013; 8: e56263. doi: 10.1371/journal.pone.0056263.
40. Battaglia C, Mancini F, Cianciosi A, Busacchi P, Facchinetti F, Marchesini GR, Marzocchi R, de Aloysio D. Vascular risk in young women with polycystic ovary and polycystic ovary syndrome. Obstet Gynecol. 2008; 111(2 pt 1): 385-395. doi: 10.1097/01.AOG.0000296657.41236.10.
41. Chekir C, Nakatsuka M, Kamada Y, Noguchi S, Sasaki A, Hiramatsu Y. Impaired uterine perfusion associated with metabolic disorders in women with polycystic ovary syndrome. Acta Obstet Gynecol Scand. 2005; 84: 189-195. doi: 10.1111/j.0001-6349.2005.00678.x.
42. Beckett EM, Astapova O, Steckler TL, Veiga-Lopez A, Padmanabhan V. Developmental programing: impact of testosterone on placental differentiation. Reproduction. 2014; 148: 199-209. doi: 10.1530/REP-14-0055.
43. Chinnathambi V, Blesson CS, Vincent KL, Saade GR, Hankins GD, Yallampalli C, Sathishkumar K. Elevated testosterone levels during rat pregnancy cause hypersensitivity to angiotensin II and attenuation of endothelium-dependent vasodilation in uterine arteries. Hypertension. 2014; 64: 405-414. doi: 10.1161/HYPERTENSIONAHA.114.03283.
44. Clifton VL. Review: sex and the human placenta: mediating differential strategies of fetal growth and survival. Placenta. 2010; (31 suppl): S33-S39. doi: 10.1016/j.placenta.2009.11.010.
45. Gabory A, Roseboom TJ, Moore T, Moore LG, Junien C. Placental contribution to the origins of sexual dimorphism in health and diseases: sex chromosomes and epigenetics. Biol Sex Differ. 2013; 4: 5. doi: 10.1186/2042-6410-4-5.
46. Chinnathambi V, More AS, Hankins GD, Yallampalli C, Sathishkumar K. Gestational exposure to elevated testosterone levels induces hypertension via heightened vascular angiotensin II type 1 receptor signaling in rats. Biol Reprod. 2014; 91: 6. doi: 10.1095/biolreprod.114.118968.
47. Blesson CS, Chinnathambi V, Hankins GD, Yallampalli C, Sathishkumar K. Prenatal testosterone exposure induces hypertension in adult females via androgen receptor-dependent protein kinase Cδ- mediated mechanism. Hypertension. 2015; 65: 683-690. doi: 10.1161/HYPERTENSIONAHA.114.04521.
48. Carlsen SM, Jacobsen G, Romundstad P. Maternal testosterone levels during pregnancy are associated with offspring size at birth. Eur J Endocrinol. 2006; 155: 365-370. doi: 10.1530/eje.1.02200.
49. Sathishkumar K, Elkins R, Yallampalli U, Balakrishnan M, Yallampalli C. Fetal programming of adult hypertension in female rat offspring exposed to androgens in utero. Early Hum Dev. 2011; 87: 407-414. doi: 10.1016/j. earlhumdev.2011.03.001.
50. Chinnathambi V, Balakrishnan M, Yallampalli C, Sathishkumar K. Prenatal testosterone exposure leads to hypertension that is gonadal hormone-dependent in adult rat male and female offspring. Biol Reprod. 2012; 137: 1-7. doi: 10.1095/biolreprod.111.097550.
51. Lee YM, Jeong CH, Koo SY, Son MJ, Song HS, Bae SK, Raleigh JA, Chung HY, Yoo MA, Kim KW. Determination of hypoxic region by hypoxia marker in developing mouse embryos in vivo: a possible signal for vessel development. Dev Dyn. 2001; 220: 175-186. doi: 10.1002/1097-0177(20010201)220: 23.0.CO; 2-F.
52. Sathishkumar K, Elkins R, Yallampalli U, Yallampalli C. Elevated androgen levels during pregnancy impair fetal growth due to placental insufficiency and programs for adult hypertension in rats. Biol Reprod. 2009; 250.
53. Hotchkiss AK, Lambright CS, Ostby JS, Parks-Saldutti L, Vandenbergh JG, Gray LE Jr. Prenatal testosterone exposure permanently masculinizes anogenital distance, nipple development, and reproductive tract morphology in female Sprague-Dawley rats. Toxicol Sci. 2007; 96: 335-345. doi: 10.1093/toxsci/kfm002.
54. Steckler T, Wang J, Bartol FF, Roy SK, Padmanabhan V. Fetal programming: prenatal testosterone treatment causes intrauterine growth retardation, reduces ovarian reserve and increases ovarian follicular recruitment. Endocrinology. 2005; 146: 3185-3193. doi: 10.1210/en.2004-1444.
55. Manikkam M, Crespi EJ, Doop DD, Herkimer C, Lee JS, Yu S, Brown MB, Foster DL, Padmanabhan V. Fetal programming: prenatal testosterone excess leads to fetal growth retardation and postnatal catch-up growth in sheep. Endocrinology. 2004; 145: 790-798. doi: 10.1210/en.2003-0478.
56. Rosenfeld CR, Morriss FH Jr, Makowski EL, Meschia G, Battaglia FC. Circulatory changes in the reproductive tissues of ewes during pregnancy. Gynecol Invest. 1974; 5: 252-268.
57. Magness RR, Rosenfeld CR. Systemic and uterine responses to alphaadrenergic stimulation in pregnant and nonpregnant ewes. Am J Obstet Gynecol. 1986; 155: 897-904.
58. Naden RP, Rosenfeld CR. Effect of angiotensin II on uterine and systemic vasculature in pregnant sheep. J Clin Invest. 1981; 68: 468-474.
59. Ross GR, Yallampalli U, Gangula PR, Reed L, Sathishkumar K, Gao H, Chauhan M, Yallampalli C. Adrenomedullin relaxes rat uterine artery: mechanisms and influence of pregnancy and estradiol. Endocrinology. 2010; 151: 4485-4493. doi: 10.1210/en.2010-0096.
60. Xiao D, Pearce WJ, Zhang L. Pregnancy enhances endothelium-dependent relaxation of ovine uterine artery: role of NO and intracellular Ca(2+). Am J Physiol Heart Circ Physiol. 2001; 281: H183-H190.
61. Palomba S, Falbo A, Russo T, Battista L, Tolino A, Orio F, Zullo F. Uterine blood flow in pregnant patients with polycystic ovary syndrome: relationships with clinical outcomes. BJOG. 2010; 117: 711-721. doi: 10.1111/j.1471-0528.2010.02525.x.
62. Palomba S, Russo T, Falbo A, Di Cello A, Amendola G, Mazza R, Tolino A, Zullo F, Tucci L, La Sala GB. Decidual endovascular trophoblast invasion in women with polycystic ovary syndrome: an experimental case-control study. J Clin Endocrinol Metab. 2012; 97: 2441-2449. doi: 10.1210/jc.2012-1100.
63. Krishna U, Bhalerao S. Placental insufficiency and fetal growth restriction. J Obstet Gynaecol India. 2011; 61: 505-511. doi: 10.1007/s13224-011-0092-x.
64. Hracsko Z, Hermesz E, Ferencz A, Orvos H, Novak Z, Pal A, Varga IS. Endothelial nitric oxide synthase is up-regulated in the umbilical cord in pregnancies complicated with intrauterine growth retardation. In Vivo. 2009; 23: 727-732.
65. Baykal C, Sargon MF, Esinler I, Onderoʇlu S, Onderoʇlu L. Placental microcirculation of intrauterine growth retarded fetuses: scanning electron microscopy of placental vascular casts. Arch Gynecol Obstet. 2004; 270: 99-103. doi: 10.1007/s00404-003-0511-z.
66. Parker AJ, Davies P, Mayho AM, Newton JR. The ultrasound estimation of sex-related variations of intrauterine growth. Am J Obstet Gynecol. 1984; 149: 665-669.
67. Ozaki T, Nishina H, Hanson MA, Poston L. Dietary restriction in pregnant rats causes gender-related hypertension and vascular dysfunction in offspring. J Physiol. 2001; 530(pt 1): 141-152.
68. Huppertz B, Peeters LL. Vascular biology in implantation and placentation. Angiogenesis. 2005; 8: 157-167. doi: 10.1007/s10456-005-9007-8.
69. Arroyo JA, Winn VD. Vasculogenesis and angiogenesis in the IUGR placenta. Semin Perinatol. 2008; 32: 172-177. doi: 10.1053/j. semperi.2008.02.006.
70. Maisonpierre PC, Suri C, Jones PF, Bartunkova S, Wiegand SJ, Radziejewski C, Compton D, McClain J, Aldrich TH, Papadopoulos N, Daly TJ, Davis S, Sato TN, Yancopoulos GD. Angiopoietin-2, a natural antagonist for Tie2 that disrupts in vivo angiogenesis. Science. 1997; 277: 55-60.
71. McMinn J, Wei M, Schupf N, Cusmai J, Johnson EB, Smith AC, Weksberg R, Thaker HM, Tycko B. Unbalanced placental expression of imprinted genes in human intrauterine growth restriction. Placenta. 2006; 27: 540-549. doi: 10.1016/j.placenta.2005.07.004.
72. Bermejo-Alvarez P, Rizos D, Rath D, Lonergan P, Gutierrez-Adan A. Sex determines the expression level of one third of the actively expressed genes in bovine blastocysts. Proc Natl Acad Sci U S A. 2010; 107: 3394-3399. doi: 10.1073/pnas.0913843107.
73. Sood R, Zehnder JL, Druzin ML, Brown PO. Gene expression patterns in human placenta. Proc Natl Acad Sci U S A. 2006; 103: 5478-5483. doi: 10.1073/pnas.0508035103.
74. Mao J, Zhang X, Sieli PT, Falduto MT, Torres KE, Rosenfeld CS. Contrasting effects of different maternal diets on sexually dimorphic gene expression in the murine placenta. Proc Natl Acad Sci U S A. 2010; 107: 5557-5562. doi: 10.1073/pnas.1000440107.
75. Shang Y, Jia Y, Sun Q, Shi W, Li R, Wang S, Sui S, Zhao R. Sexually dimorphic effects of maternal dietary protein restriction on fetal growth and placental expression of 11β-HSD2 in the pig. Anim Reprod Sci. 2015; 160: 40-48. doi: 10.1016/j.anireprosci.2015. 07.001.
76. Gheorghe CP, Goyal R, Mittal A, Longo LD. Gene expression in the placenta: maternal stress and epigenetic responses. Int J Dev Biol. 2010; 54: 507-523. doi: 10.1387/ijdb.082770cg.
77. Gheorghe C, Mohan S, Longo LD. Gene expression patterns in the developing murine placenta. J Soc Gynecol Investig. 2006; 13: 256-262. doi: 10.1016/j.jsgi.2006.02.007.