Adverse Intrauterine Environment and Gamete/Embryo-Fetal Origins of Diseases

  • Min-Yue Dong
  • Fang-Fang Wang
  • Jie-Xue Pan
  • He-Feng Huang


The ‘fetal origins of adult disease (FOAD)’ hypothesis proposes that developmental programming during gestation may influence adult health and disease [1]. It suggests a process where events occurring at critical, or sensitive, periods of fetal development, permanently alter structure, physiology, or metabolism. These changes predispose affected individuals to diseases in later life.

Barker and his colleagues were the first to develop the concept of FOAD based on significant associations between low birthweight and the risk of chronic diseases in adulthood, including coronary artery disease, hypertension and stroke, type 2 diabetes, and osteoporosis. Several other groups confirmed associations between birthweight and adult health in other populations. These adverse intrauterine environments include gestational diabetes mellitus (GDM), intrauterine undernutrition and pre-eclampsia, which are common and severe gestational complications. Furthermore, certain antenatal nutritional disturbances can increase the risk of diseases later in life without affecting fetal growth. In this chapter, we will discuss the evidence related to adverse intrauterine environment and embryo-fetal origins of diseases.


Gestational Diabetes Mellitus Severe Preeclampsia Antiangiogenic Factor Maternal Undernutrition Preeclamptic Pregnancy 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. 1.
    Barker DJ. The fetal and infant origins of disease. Eur J Clin Invest. 1995;25:457–63.PubMedCrossRefGoogle Scholar
  2. 2.
    King H. Epidemiology of glucose intolerance and gestational diabetes in women of childbearing age. Diabetes Care. 1998;21 Suppl 2:B9–13.PubMedGoogle Scholar
  3. 3.
    Shah BR, Retnakaran R, Booth GL. Increased risk of cardiovascular disease in young women following gestational diabetes mellitus. Diabetes Care. 2008;31:1668–9.PubMedCentralPubMedCrossRefGoogle Scholar
  4. 4.
    Carr DB, Utzschneider KM, Hull RL, et al. Gestational diabetes mellitus increases the risk of cardiovascular disease in women with a family history of type 2 diabetes. Diabetes Care. 2006;29:2078–83.PubMedCrossRefGoogle Scholar
  5. 5.
    Barker DJ, Winter PD, Osmond C, et al. Weight in infancy and death from ischaemic heart disease. Lancet. 1989;2:577–80.PubMedCrossRefGoogle Scholar
  6. 6.
    Barker DJ, Gluckman PD, Godfrey KM, et al. Fetal nutrition and cardiovascular disease in adult life. Lancet. 1993;341:938–41.PubMedCrossRefGoogle Scholar
  7. 7.
    Stein CE, Fall CH, Kumaran K, et al. Fetal growth and coronary heart disease in south India. Lancet. 1996;348:1269–73.PubMedCrossRefGoogle Scholar
  8. 8.
    Barker DJ, Hales CN, Fall CH, et al. Type 2 (non-insulin-dependent) diabetes mellitus, hypertension and hyperlipidaemia (syndrome X): relation to reduced fetal growth. Diabetologia. 1993;36:62–7.PubMedCrossRefGoogle Scholar
  9. 9.
    Vickers MH, Breier BH, Cutfield WS, et al. Fetal origins of hyperphagia, obesity, and hypertension and postnatal amplification by hypercaloric nutrition. Am J Physiol Endocrinol Metab. 2000;279:E83–7.PubMedGoogle Scholar
  10. 10.
    Phillips DI. Insulin resistance as a programmed response to fetal undernutrition. Diabetologia. 1996;39:1119–22.PubMedCrossRefGoogle Scholar
  11. 11.
    McMillen IC, Robinson JS. Developmental origins of the metabolic syndrome: prediction, plasticity, and programming. Physiol Rev. 2005;85:571–633.PubMedCrossRefGoogle Scholar
  12. 12.
    Leon DA, Lithell HO, Vagero D, et al. Reduced fetal growth rate and increased risk of death from ischaemic heart disease: cohort study of 15 000 Swedish men and women born 1915–29. BMJ. 1998;317:241–5.PubMedCentralPubMedCrossRefGoogle Scholar
  13. 13.
    de Rooij SR, Painter RC, Holleman F, et al. The metabolic syndrome in adults prenatally exposed to the Dutch famine. Am J Clin Nutr. 2007;86:1219–24.PubMedGoogle Scholar
  14. 14.
    Levitt NS, Lambert EV, Woods D, et al. Impaired glucose tolerance and elevated blood pressure in low birth weight, nonobese, young South African adults: early programming of cortisol axis. J Clin Endocrinol Metab. 2000;85:4611–18.PubMedGoogle Scholar
  15. 15.
    Yajnik CS. Early life origins of insulin resistance and type 2 diabetes in India and other Asian countries. J Nutr. 2004;134:205–10.PubMedGoogle Scholar
  16. 16.
    Chernausek SD. Update: consequences of abnormal fetal growth. J Clin Endocrinol Metab. 2012;97:689–95.PubMedCentralPubMedCrossRefGoogle Scholar
  17. 17.
    Black HR. The paradigm has shifted to systolic blood pressure. J Hum Hypertens. 2004;18 Suppl 2:S3–7.PubMedCrossRefGoogle Scholar
  18. 18.
    Kingwell BA, Gatzka CD. Arterial stiffness and prediction of cardiovascular risk. J Hypertens. 2002;20:2337–40.PubMedCrossRefGoogle Scholar
  19. 19.
    Tzschoppe A, Struwe E, Rascher W, et al. Intrauterine growth restriction (IUGR) is associated with increased leptin synthesis and binding capability in neonates. Clin Endocrinol (Oxf). 2011;74:459–66.CrossRefGoogle Scholar
  20. 20.
    Spiegelman BM, Choy L, Hotamisligil GS, et al. Regulation of adipocyte gene expression in differentiation and syndromes of obesity/diabetes. J Biol Chem. 1993;268:6823–6.PubMedGoogle Scholar
  21. 21.
    Tsubahara M, Shoji H, Mori M, et al. Glucose metabolism soon after birth in very premature infants with small- and appropriate-for-gestational-age birth weights. Early Hum Dev. 2012;88:735–8.PubMedCrossRefGoogle Scholar
  22. 22.
    Leeson CP, Whincup PH, Cook DG, et al. Flow-mediated dilation in 9- to 11-year-old children: the influence of intrauterine and childhood factors. Circulation. 1997;96:2233–8.PubMedCrossRefGoogle Scholar
  23. 23.
    Goodfellow J, Bellamy MF, Gorman ST, et al. Endothelial function is impaired in fit young adults of low birth weight. Cardiovasc Res. 1998;40:600–6.PubMedCrossRefGoogle Scholar
  24. 24.
    Martin H, Hu J, Gennser G, et al. Impaired endothelial function and increased carotid stiffness in 9-year-old children with low birthweight. Circulation. 2000;102:2739–44.PubMedCrossRefGoogle Scholar
  25. 25.
    McAllister AS, Atkinson AB, Johnston GD, et al. Relationship of endothelial function to birth weight in humans. Diabetes Care. 1999;22:2061–6.PubMedCrossRefGoogle Scholar
  26. 26.
    Wilkinson IB, Cockcroft JR. Commentary: birthweight arterial stiffness and blood pressure: in search of a unifying hypothesis. Int J Epidemiol. 2004;33:161–2.PubMedCrossRefGoogle Scholar
  27. 27.
    Antonios TF, Singer DR, Markandu ND, et al. Rarefaction of skin capillaries in borderline essential hypertension suggests an early structural abnormality. Hypertension. 1999;34:655–8.PubMedCrossRefGoogle Scholar
  28. 28.
    Broyd C, Harrison E, Raja M, et al. Association of pulse waveform characteristics with birth weight in young adults. J Hypertens. 2005;23:1391–6.PubMedCrossRefGoogle Scholar
  29. 29.
    Armitage JA, Khan IY, Taylor PD, et al. Developmental programming of the metabolic syndrome by maternal nutritional imbalance: how strong is the evidence from experimental models in mammals? J Physiol. 2004;561:355–77.PubMedCentralPubMedCrossRefGoogle Scholar
  30. 30.
    Limesand SW, Rozance PJ, Zerbe GO, et al. Attenuated insulin release and storage in fetal sheep pancreatic islets with intrauterine growth restriction. Endocrinology. 2006;147:1488–97.PubMedCrossRefGoogle Scholar
  31. 31.
    Hales CN, Ozanne SE. For debate: Fetal and early postnatal growth restriction lead to diabetes, the metabolic syndrome and renal failure. Diabetologia. 2003;46:1013–19.PubMedCrossRefGoogle Scholar
  32. 32.
    Coupe B, Grit I, Hulin P, et al. Postnatal growth after intrauterine growth restriction alters central leptin signal and energy homeostasis. PLoS One. 2012;7:e30616.PubMedCentralPubMedCrossRefGoogle Scholar
  33. 33.
    Bar-El Dadon S, Shahar R, Katalan V, et al. Leptin administration affects growth and skeletal development in a rat intrauterine growth restriction model: preliminary study. Nutrition. 2011;27:973–7.PubMedCrossRefGoogle Scholar
  34. 34.
    Brawley L, Itoh S, Torrens C, et al. Dietary protein restriction in pregnancy induces hypertension and vascular defects in rat male offspring. Pediatr Res. 2003;54:83–90.PubMedCrossRefGoogle Scholar
  35. 35.
    Torrens C, Brawley L, Barker AC, et al. Maternal protein restriction in the rat impairs resistance artery but not conduit artery function in pregnant offspring. J Physiol. 2003;547:77–84.PubMedCentralPubMedCrossRefGoogle Scholar
  36. 36.
    Lamireau D, Nuyt AM, Hou X, et al. Altered vascular function in fetal programming of hypertension. Stroke. 2002;33:2992–8.PubMedCrossRefGoogle Scholar
  37. 37.
    Rueda-Clausen CF, Morton JS, Lopaschuk GD, et al. Long-term effects of intrauterine growth restriction on cardiac metabolism and susceptibility to ischaemia/reperfusion. Cardiovasc Res. 2011;90:285–94.PubMedCrossRefGoogle Scholar
  38. 38.
    Remacle C, Bieswal F, Bol V, et al. Developmental programming of adult obesity and cardiovascular disease in rodents by maternal nutrition imbalance. Am J Clin Nutr. 2011;94:1846S–52.PubMedCrossRefGoogle Scholar
  39. 39.
    Choi GY, Tosh DN, Garg A, et al. Gender-specific programmed hepatic lipid dysregulation in intrauterine growth-restricted offspring. Am J Obstet Gynecol. 2007;196:477 e471–7.Google Scholar
  40. 40.
    Osterholm EA, Hostinar CE, Gunnar MR. Alterations in stress responses of the hypothalamic-pituitary-adrenal axis in small for gestational age infants. Psychoneuroendocrinology. 2012;37:1719–25.PubMedCrossRefGoogle Scholar
  41. 41.
    Gluckman PD, Hanson MA, Cooper C, et al. Effect of in utero and early-life conditions on adult health and disease. N Engl J Med. 2008;359:61–73.PubMedCentralPubMedCrossRefGoogle Scholar
  42. 42.
    Gluckman PD, Lillycrop KA, Vickers MH, et al. Metabolic plasticity during mammalian development is directionally dependent on early nutritional status. Proc Natl Acad Sci U S A. 2007;104:12796–800.PubMedCentralPubMedCrossRefGoogle Scholar
  43. 43.
    Godfrey KM, Gluckman PD, Hanson MA. Developmental origins of metabolic disease: life course and intergenerational perspectives. Trends Endocrinol Metab. 2010;21:199–205.PubMedCrossRefGoogle Scholar
  44. 44.
    Goldberg AD, Allis CD, Bernstein E. Epigenetics: a landscape takes shape. Cell. 2007;128:635–8.PubMedCrossRefGoogle Scholar
  45. 45.
    Gluckman PD, Hanson MA, Buklijas T, et al. Epigenetic mechanisms that underpin metabolic and cardiovascular diseases. Nat Rev Endocrinol. 2009;5:401–8.PubMedCrossRefGoogle Scholar
  46. 46.
    Diplas AI, Lambertini L, Lee MJ, et al. Differential expression of imprinted genes in normal and IUGR human placentas. Epigenetics. 2009;4:235–40.PubMedCrossRefGoogle Scholar
  47. 47.
    Einstein F, Thompson RF, Bhagat TD, et al. Cytosine methylation dysregulation in neonates following intrauterine growth restriction. PLoS One. 2010;5:e8887.PubMedCentralPubMedCrossRefGoogle Scholar
  48. 48.
    Roth CL, Sathyanarayana S. Mechanisms affecting neuroendocrine and epigenetic regulation of body weight and onset of puberty: potential implications in the child born small for gestational age (SGA). Rev Endocr Metab Disord. 2012;13:129–40.PubMedCrossRefGoogle Scholar
  49. 49.
    Banister CE, Koestler DC, Maccani MA, et al. Infant growth restriction is associated with distinct patterns of DNA methylation in human placentas. Epigenetics. 2011;6:920–7.PubMedCentralPubMedCrossRefGoogle Scholar
  50. 50.
    Uzan J, Carbonnel M, Piconne O, et al. Pre-eclampsia: pathophysiology, diagnosis, and management. Vasc Health Risk Manag. 2011;7:467–74.PubMedCentralPubMedGoogle Scholar
  51. 51.
    Geelhoed JJ, Fraser A, Tilling K, et al. Preeclampsia and gestational hypertension are associated with childhood blood pressure independently of family adiposity measures: the Avon Longitudinal Study of Parents and Children. Circulation. 2010;122:1192–9.PubMedCrossRefGoogle Scholar
  52. 52.
    Wen X, Triche EW, Hogan JW, et al. Prenatal factors for childhood blood pressure mediated by intrauterine and/or childhood growth? Pediatrics. 2011;127:e713–21.PubMedCentralPubMedCrossRefGoogle Scholar
  53. 53.
    Jayet PY, Rimoldi SF, Stuber T, et al. Pulmonary and systemic vascular dysfunction in young offspring of mothers with preeclampsia. Circulation. 2010;122:488–94.PubMedCrossRefGoogle Scholar
  54. 54.
    Kajantie E, Eriksson JG, Osmond C, et al. Pre-eclampsia is associated with increased risk of stroke in the adult offspring: the Helsinki birth cohort study. Stroke. 2009;40:1176–80.PubMedCrossRefGoogle Scholar
  55. 55.
    Wu CS, Sun Y, Vestergaard M, et al. Preeclampsia and risk for epilepsy in offspring. Pediatrics. 2008;122:1072–8.PubMedCrossRefGoogle Scholar
  56. 56.
    Tamimi R, Lagiou P, Vatten LJ, et al. Pregnancy hormones, pre-eclampsia, and implications for breast cancer risk in the offspring. Cancer Epidemiol Biomarkers Prev. 2003;12:647–50.PubMedGoogle Scholar
  57. 57.
    Wu CS, Nohr EA, Bech BH, et al. Health of children born to mothers who had preeclampsia: a population-based cohort study. Am J Obstet Gynecol. 2009;201:269 e1–10.CrossRefGoogle Scholar
  58. 58.
    Davis EF, Lazdam M, Lewandowski AJ, et al. Cardiovascular risk factors in children and young adults born to preeclamptic pregnancies: a systematic review. Pediatrics. 2012;129:e1552–61.PubMedCrossRefGoogle Scholar
  59. 59.
    Lawlor DA, Macdonald-Wallis C, Fraser A, et al. Cardiovascular biomarkers and vascular function during childhood in the offspring of mothers with hypertensive disorders of pregnancy: findings from the Avon Longitudinal Study of Parents and Children. Eur Heart J. 2012;33:335–45.PubMedCentralPubMedCrossRefGoogle Scholar
  60. 60.
    Ogland B, Vatten LJ, Romundstad PR, et al. Pubertal anthropometry in sons and daughters of women with preeclamptic or normotensive pregnancies. Arch Dis Child. 2009;94:855–9.PubMedCrossRefGoogle Scholar
  61. 61.
    Ros HS, Lichtenstein P, Ekbom A, et al. Tall or short? Twenty years after preeclampsia exposure in utero: comparisons of final height, body mass index, waist-to-hip ratio, and age at menarche among women, exposed and unexposed to preeclampsia during fetal life. Pediatr Res. 2001;49:763–9.PubMedCrossRefGoogle Scholar
  62. 62.
    Trichopoulos D. Hypothesis: does breast cancer originate in utero? Lancet. 1990;335:939–40.PubMedCrossRefGoogle Scholar
  63. 63.
    Garoff L, Seppala M. Toxemia of pregnancy: assessment of fetal distress by urinary estriol and circulating human placental lactogen and alpha-fetoprotein levels. Am J Obstet Gynecol. 1976;126:1027–33.PubMedGoogle Scholar
  64. 64.
    Troisi R, Potischman N, Roberts JM, et al. Maternal serum oestrogen and androgen concentrations in preeclamptic and uncomplicated pregnancies. Int J Epidemiol. 2003;32:455–60.PubMedCrossRefGoogle Scholar
  65. 65.
    Vatten LJ, Romundstad PR, Odegard RA, et al. Alpha-foetoprotein in umbilical cord in relation to severe pre-eclampsia, birth weight and future breast cancer risk. Br J Cancer. 2002;86:728–31.PubMedCentralPubMedCrossRefGoogle Scholar
  66. 66.
    Acromite MT, Mantzoros CS, Leach RE, et al. Androgens in preeclampsia. Am J Obstet Gynecol. 1999;180:60–3.PubMedCrossRefGoogle Scholar
  67. 67.
    Ekbom A, Wuu J, Adami HO, et al. Duration of gestation and prostate cancer risk in offspring. Cancer Epidemiol Biomarkers Prev. 2000;9:221–3.PubMedGoogle Scholar
  68. 68.
    Troisi R, Potischman N, Hoover RN. Exploring the underlying hormonal mechanisms of prenatal risk factors for breast cancer: a review and commentary. Cancer Epidemiol Biomarkers Prev. 2007;16:1700–12.PubMedCrossRefGoogle Scholar
  69. 69.
    Libby G, Murphy DJ, McEwan NF, et al. Pre-eclampsia and the later development of type 2 diabetes in mothers and their children: an intergenerational study from the Walker cohort. Diabetologia. 2007;50:523–30.PubMedCrossRefGoogle Scholar
  70. 70.
    Tenhola S, Rahiala E, Martikainen A, et al. Blood pressure, serum lipids, fasting insulin, and adrenal hormones in 12-year-old children born with maternal preeclampsia. J Clin Endocrinol Metab. 2003;88:1217–22.PubMedCrossRefGoogle Scholar
  71. 71.
    Badawi N, Kurinczuk JJ, Keogh JM, et al. Antepartum risk factors for newborn encephalopathy: the Western Australian case–control study. BMJ. 1998;317:1549–53.PubMedCentralPubMedCrossRefGoogle Scholar
  72. 72.
    McCarthy FP, Kingdom JC, Kenny LC, et al. Animal models of preeclampsia; uses and limitations. Placenta. 2011;32:413–19.PubMedCrossRefGoogle Scholar
  73. 73.
    Huizinga CT, Engelbregt MJ, Rekers-Mombarg LT, et al. Ligation of the uterine artery and early postnatal food restriction – animal models for growth retardation. Horm Res. 2004;62:233–40.PubMedCrossRefGoogle Scholar
  74. 74.
    Soleymanlou N, Jurisica I, Nevo O, et al. Molecular evidence of placental hypoxia in preeclampsia. J Clin Endocrinol Metab. 2005;90:4299–308.PubMedCrossRefGoogle Scholar
  75. 75.
    Cheng MH, Wang PH. Placentation abnormalities in the pathophysiology of preeclampsia. Expert Rev Mol Diagn. 2009;9:37–49.PubMedCrossRefGoogle Scholar
  76. 76.
    Lai Z, Kalkunte S, Sharma S. A critical role of interleukin-10 in modulating hypoxia-induced preeclampsia-like disease in mice. Hypertension. 2011;57:505–14.PubMedCentralPubMedCrossRefGoogle Scholar
  77. 77.
    Luttun A, Carmeliet P. Soluble VEGF receptor Flt1: the elusive preeclampsia factor discovered? J Clin Invest. 2003;111:600–2.PubMedCentralPubMedCrossRefGoogle Scholar
  78. 78.
    Venkatesha S, Toporsian M, Lam C, et al. Soluble endoglin contributes to the pathogenesis of preeclampsia. Nat Med. 2006;12:642–9.PubMedCrossRefGoogle Scholar
  79. 79.
    Lu F, Bytautiene E, Tamayo E, et al. Gender-specific effect of overexpression of sFlt-1 in pregnant mice on fetal programming of blood pressure in the offspring later in life. Am J Obstet Gynecol. 2007;197:418 e411–5.CrossRefGoogle Scholar
  80. 80.
    Maynard SE, Min JY, Merchan J, et al. Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia. J Clin Invest. 2003;111:649–58.PubMedCentralPubMedCrossRefGoogle Scholar
  81. 81.
    Van Vliet BN, Chafe LL. Maternal endothelial nitric oxide synthase genotype influences offspring blood pressure and activity in mice. Hypertension. 2007;49:556–62.PubMedCrossRefGoogle Scholar
  82. 82.
    McMullen S, Langley-Evans SC. Sex-specific effects of prenatal low-protein and carbenoxolone exposure on renal angiotensin receptor expression in rats. Hypertension. 2005;46:1374–80.PubMedCentralPubMedCrossRefGoogle Scholar
  83. 83.
    O’Regan D, Kenyon CJ, Seckl JR, et al. Glucocorticoid exposure in late gestation in the rat permanently programs gender-specific differences in adult cardiovascular and metabolic physiology. Am J Physiol Endocrinol Metab. 2004;287:E863–70.PubMedCrossRefGoogle Scholar
  84. 84.
    Mazzuca MQ, Wlodek ME, Dragomir NM, et al. Uteroplacental insufficiency programs regional vascular dysfunction and alters arterial stiffness in female offspring. J Physiol. 2010;588:1997–2010.PubMedCentralPubMedCrossRefGoogle Scholar
  85. 85.
    Wang Z, Huang Z, Lu G, et al. Hypoxia during pregnancy in rats leads to early morphological changes of atherosclerosis in adult offspring. Am J Physiol Heart Circ Physiol. 2009;296:H1321–8.PubMedCrossRefGoogle Scholar
  86. 86.
    Pascoe KC, Wlodek ME, Jones GT. Increased elastic tissue defect formation in the growth restricted Brown Norway rat: a potential link between in utero condition and cardiovascular disease. Pediatr Res. 2008;64:125–30.PubMedCrossRefGoogle Scholar
  87. 87.
    Akcakus M, Altunay L, Yikilmaz A, et al. The relationship between abdominal aortic intima-media thickness and lipid profile in neonates born to mothers with preeclampsia. J Pediatr Endocrinol Metab. 2010;23:1143–9.PubMedCrossRefGoogle Scholar
  88. 88.
    Davis EF, Newton L, Lewandowski AJ, et al. Pre-eclampsia and offspring cardiovascular health: mechanistic insights from experimental studies. Clin Sci (Lond). 2012;123:53–72.CrossRefGoogle Scholar
  89. 89.
    Bae S, Xiao Y, Li G, et al. Effect of maternal chronic hypoxic exposure during gestation on apoptosis in fetal rat heart. Am J Physiol Heart Circ Physiol. 2003;285:H983–90.PubMedGoogle Scholar
  90. 90.
    Li G, Xiao Y, Estrella JL, et al. Effect of fetal hypoxia on heart susceptibility to ischemia and reperfusion injury in the adult rat. J Soc Gynecol Investig. 2003;10:265–74.PubMedCrossRefGoogle Scholar
  91. 91.
    Patterson AJ, Chen M, Xue Q, et al. Chronic prenatal hypoxia induces epigenetic programming of PKC{epsilon} gene repression in rat hearts. Circ Res. 2010;107:365–73.PubMedCentralPubMedCrossRefGoogle Scholar
  92. 92.
    Budas GR, Mochly-Rosen D. Mitochondrial protein kinase Cepsilon (PKCepsilon): emerging role in cardiac protection from ischaemic damage. Biochem Soc Trans. 2007;35:1052–4.PubMedCrossRefGoogle Scholar
  93. 93.
    Kvehaugen AS, Dechend R, Ramstad HB, et al. Endothelial function and circulating biomarkers are disturbed in women and children after preeclampsia. Hypertension. 2011;58:63–9.PubMedCrossRefGoogle Scholar
  94. 94.
    Wang Y, Zhou Y, He L, et al. Gene delivery of soluble vascular endothelial growth factor receptor-1 (sFlt-1) inhibits intra-plaque angiogenesis and suppresses development of atherosclerotic plaque. Clin Exp Med. 2011;11:113–21.PubMedCrossRefGoogle Scholar
  95. 95.
    Moyes AJ, Maldonado-Perez D, Gray GA, et al. Enhanced angiogenic capacity of human umbilical vein endothelial cells from women with preeclampsia. Reprod Sci. 2011;18:374–82.PubMedCrossRefGoogle Scholar
  96. 96.
    Medica I, Kastrin A, Peterlin B. Genetic polymorphisms in vasoactive genes and preeclampsia: a meta-analysis. Eur J Obstet Gynecol Reprod Biol. 2007;131:115–26.PubMedCrossRefGoogle Scholar
  97. 97.
    Yu CK, Casas JP, Savvidou MD, et al. Endothelial nitric oxide synthase gene polymorphism (Glu298Asp) and development of pre-eclampsia: a case–control study and a meta-analysis. BMC Pregnancy Childbirth. 2006;6:7.PubMedCentralPubMedCrossRefGoogle Scholar
  98. 98.
    Odom LN, Taylor HS. Environmental induction of the fetal epigenome. Expert Rev Obstet Gynecol. 2010;5:657–64.PubMedCentralPubMedCrossRefGoogle Scholar
  99. 99.
    von Zglinicki T. Oxidative stress shortens telomeres. Trends Biochem Sci. 2002;27:339–44.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2014

Authors and Affiliations

  • Min-Yue Dong
    • 1
    • 2
  • Fang-Fang Wang
    • 1
    • 2
  • Jie-Xue Pan
    • 1
    • 2
  • He-Feng Huang
    • 1
    • 2
  1. 1.The Key Laboratory of Reproductive GeneticsZhejiang University, Ministry of EducationHangzhouPeople’s Republic of China
  2. 2.Department of Reproductive EndocrinologyWomen’s Hospital, School of Medicine, Zhejiang UniversityHangzhouPeople’s Republic of China

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