Altered Endothelial Nitric Oxide Signaling as a Paradigm for Maternal Vascular Maladaptation in Preeclampsia

Preeclampsia (VD Garovic, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Preeclampsia

Abstract

Purpose of Review

The goal of this review is to present the newest insights into what we view as a central failure of cardiovascular adaptation in preeclampsia (PE) by focusing on one clinically significant manifestation of maternal endothelial dysfunction: nitric oxide signaling. The etiology, symptoms, and current theories of the PE syndrome are described first, followed by a review of the available evidence, and underlying causes of reduced endothelial nitric oxide (NO) signaling in PE.

Recent Findings

PE maladaptations include, but are not limited to, altered physiological stimulatory inputs (e.g., estrogen; VEGF/PlGF; shear stress) and substrates (L-Arg; ADMA), augmented placental secretion of anti-angiogenic and inflammatory factors such as sFlt-1 and Eng, changes in eNOS (polymorphisms, expression), and reduced bioavailability of NO secondary to oxidative stress.

Summary

PE is a complex obstetrical syndrome that is associated with maternal vascular dysfunction. Diminished peripheral endothelial vasodilator influence in general, and of NO signaling specifically, are key in driving disease progression and severity.

Keywords

Preeclampsia Nitric oxide Nitric oxide synthase Vascular tone Endothelial dysfunction Vasodilation, 

Abbreviations

2-ME

2-Methoxyestradiol

ADMA

Asymmetric dimethyl arginine

AT1

Angiotensin type 1 receptor

AT2

Angiotensin type 2 receptor

BH4

Tetrahydrobiopterin

CaM

Calmodulin

cGMP

Cyclic guanosine 3′,5′ monophosphate

DDAH

Dimethylarginine dimethylaminohydrolase

ECE

Endothelin converting enzyme

EDH

Endothelium-derived hyperpolarizing factor

EDRF

Endothelium-derived relaxing factor

ET

Endothelin

ETA

Endothelin A receptor

ETB

Endothelin B receptor

eNOS/NOS3

Endothelial nitric oxide synthase

ERα

Estrogen receptor-α

ERß

Estrogen receptor-ß

ERRϒ

Estrogen-related receptor ϒ

FAD

Flavin adenine dinucleotide

FMD

Flow-mediated dilation

FMN

Flavin mononucleotide

Gi

Gi-coupled receptor

GPER

G-protein-coupled estrogen receptor

HO-1

Heme oxygenase-1

iNOS/NOS2

Cytokine-inducible nitric oxide synthase

nNOS/NOS1

Neuronal nitric oxide synthase

L-Arg

L-arginine

LOX-1

Lectin-like oxidized LDL receptor-1

NADPH

Nicotinamide adenine dinucleotide phosphate

NO

Nitric oxide

oxLDL

Oxidized low-density lipoproteins

P2Y

Purinergic G protein-coupled receptor

PE

Preeclampsia

PlGF

Placental growth factor

PRMT

S-adenylmethionine-dependent methyltransferase

ROS

Reactive oxygen species

RUPP

Reduced uterine perfusion pressure

sEng

Soluble endoglin

sFlt-1

Soluble fms-like tyrosine kinase-1 receptor

SIRT-1

Silent mating-type information regulation 2 homolog 1

SOD

Superoxide dismutases

STBEV

Syncytiotrophoblast extracellular vesicle

TRPV1

Transient receptor potential cation channel subfamily V member 1

TRPV4

Transient receptor potential cation channel subfamily V member 4

VEGF

Vascular endothelial growth factor

VEGFR1

VEGF receptor 1, Flt1

VEGFR2

VEGF receptor 2, KDR

Notes

Compliance with Ethical Standards

Conflict of Interest

The authors declare no conflicts of interest relevant to this manuscript.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

References

Papers of particular interest, published recently, have been highlighted as: • Of importance

  1. 1.
    • Osol G, Bernstein I. Preeclampsia and maternal cardiovascular disease: consequence or predisposition? J Vasc Res. 2014;51(4):290–304. A paper that considers whether long-term health consequences of PE on a woman’s cardiovascular health result from the disease, or if the disease results from a phenotype that already has some cardiovascular damage, so that the stress of pregnancy results in maladptation and leads to the symptoms of PE. PubMedCrossRefGoogle Scholar
  2. 2.
    • Brosens I. A study of the spiral arteries of the decidua basalis in normotensive and hypertensive pregnancies. J Obstet Gynaecol Br Commonw. 1964;71:222–30. Initial observation of shallow spiral artery invasion in PE women more than 50 years ago. PubMedCrossRefGoogle Scholar
  3. 3.
    Karumanchi SA. Angiogenic factors in preeclampsia: from diagnosis to therapy. Hypertension. 2016;67(6):1072–9.PubMedCrossRefGoogle Scholar
  4. 4.
    Roberts JM, Hubel CA. The two stage model of preeclampsia: variations on the theme. Placenta. 2009;30(Suppl A):S32–7.PubMedCrossRefGoogle Scholar
  5. 5.
    Van Wijk MJ, et al. Vascular function in preeclampsia. Cardiovasc Res. 2000;47(1):38–48.CrossRefGoogle Scholar
  6. 6.
    Roberts JM, Bell MJ. If we know so much about preeclampsia, why haven't we cured the disease? J Reprod Immunol. 2013;99(1–2):1–9.PubMedPubMedCentralCrossRefGoogle Scholar
  7. 7.
    Myatt L, Roberts JM. Preeclampsia: syndrome or disease? Curr Hypertens Rep. 2015;17(11):83.PubMedCrossRefGoogle Scholar
  8. 8.
    Lyall F, Robson SC, Bulmer JN. Spiral artery remodeling and trophoblast invasion in preeclampsia and fetal growth restriction: relationship to clinical outcome. Hypertension. 2013;62(6):1046–54.PubMedCrossRefGoogle Scholar
  9. 9.
    Burke SD, et al. Spiral arterial remodeling is not essential for normal blood pressure regulation in pregnant mice. Hypertension. 2010;55(3):729–37.PubMedPubMedCentralCrossRefGoogle Scholar
  10. 10.
    • Huppertz B, Weiss G, Moser G. Trophoblast invasion and oxygenation of the placenta: measurements versus presumptions. J Reprod Immunol. 2014;101-102:74–9. Challenges the theory that poor trophoblast invasion leads to placental hypoxia and invites the reader to rethink the hypothesis that has almost become dogma in terms of the pathogenesis of PE. PubMedCrossRefGoogle Scholar
  11. 11.
    Bernstein IM, et al. Intolerance to volume expansion: a theorized mechanism for the development of preeclampsia. Obstet Gynecol. 1998;92(2):306–8.PubMedGoogle Scholar
  12. 12.
    Hutchinson ES, et al. Utero-placental haemodynamics in the pathogenesis of pre-eclampsia. Placenta. 2009;30(7):634–41.PubMedCrossRefGoogle Scholar
  13. 13.
    Gonska BD, Bethge KP, Kreuzer H. Spontaneous and stimulus-induced arrhythmia behavior in dilated cardiomyopathy. Z Kardiol. 1987;76(9):546–53.PubMedGoogle Scholar
  14. 14.
    Nasiri R, et al. Association of meteorological factors and seasonality with preeclampsia: a 5-year study in northeast of Iran. Clin Exp Hypertens. 2014;36(8):586–9.PubMedCrossRefGoogle Scholar
  15. 15.
    George EM. New approaches for managing preeclampsia: clues from clinical and basic research. Clin Ther. 2014;36(12):1873–81.PubMedPubMedCentralCrossRefGoogle Scholar
  16. 16.
    Boeldt DS, Bird IM. Vascular adaptation in pregnancy and endothelial dysfunction in preeclampsia. J Endocrinol. 2017;232(1):R27–44.PubMedCrossRefGoogle Scholar
  17. 17.
    • Osol G, et al. Placental growth factor is a potent vasodilator of rat and human resistance arteries. Am J Physiol Heart Circ Physiol. 2008;294(3):H1381–7. Our study describing the vasoactive effects of PlGF (and, therefore, of the VEGFR1/Flt-1 endothelial receptor) in isolated vessels from humans and rats, showing that it is a potent vasodilator and that its action derives largely from stimulation NO production. PubMedPubMedCentralCrossRefGoogle Scholar
  18. 18.
    • Cross SN, et al. Bevacizumab-mediated interference with VEGF signaling is sufficient to induce a preeclampsia-like syndrome in nonpregnant women. Rev Obstet Gynecol. 2012;5(1):2–8. This paper is notable in its demonstration that a preeclampsia-like condition (hypertension, proteinuria) can be induced in nonpregnant women simply by taking an antibody that binds VEGF, much like sFlt-1. PubMedPubMedCentralGoogle Scholar
  19. 19.
    Svedas E, et al. Vascular endothelial growth factor induced functional and morphologic signs of endothelial dysfunction in isolated arteries from normal pregnant women. Am J Obstet Gynecol. 2003;188(1):168–76.PubMedCrossRefGoogle Scholar
  20. 20.
    Magness RR, et al. Endothelial vasodilator production by uterine and systemic arteries. V. Effects of ovariectomy, the ovarian cycle, and pregnancy on prostacyclin synthase expression. Prostaglandins Other Lipid Mediat, 2000. 60(4-6):103-18.Google Scholar
  21. 21.
    Sheibani L, et al. Augmented H2S production via cystathionine-beta-synthase upregulation plays a role in pregnancy-associated uterine vasodilation. Biol Reprod, 2017. 96(3): p. 664-672.Google Scholar
  22. 22.
    Gokina NI, Kuzina OY, Vance AM. Augmented EDHF signaling in rat uteroplacental vasculature during late pregnancy. Am J Physiol Heart Circ Physiol, 2010. 299(5): p. H1642-52.Google Scholar
  23. 23.
    Gokina NI, Goecks T. Upregulation of endothelial cell Ca2+ signaling contributes to pregnancy-enhanced vasodilation of rat uteroplacental arteries. Am J Physiol Heart Circ Physiol, 2006. 290(5):H2124-35.Google Scholar
  24. 24.
    Steinert JR, et al. Redox modulation of Ca2+ signaling in human endothelial and smooth muscle cells in pre-eclampsia. Antioxid Redox Signal, 2009. 11(5): p. 1149-63.Google Scholar
  25. 25.
    • Furchgott RF, Zawadzk JV. The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature, 1980. 288(5789): p. 373-6. A classic paper, the first discovery that the endothelium exerts a vasodilatory influence on vascular smooth muscle in response to cholinergic stimulation. PubMedCrossRefGoogle Scholar
  26. 26.
    Furchgott RF. The 1996 Albert Lasker medical research awards. The discovery of endothelium-derived relaxing factor and its importance in the identification of nitric oxide. JAMA. 1996;276(14):1186–8.PubMedCrossRefGoogle Scholar
  27. 27.
    • Osol G, et al. Inhibition of nitric oxide synthases abrogates pregnancy-induced uterine vascular expansive remodeling. J Vasc Res. 2009;46(5):478–86. Description of how systemic eNOS inhibition with L-NAME attenuates expansive remodeling of uterine vessels in pregnant rats, implicating NO in maternal uterine vascular remodeling during pregnancy. PubMedPubMedCentralCrossRefGoogle Scholar
  28. 28.
    Hale SA, et al. Reduced NO signaling during pregnancy attenuates outward uterine artery remodeling by altering MMP expression and collagen and elastin deposition. Am J Physiol Heart Circ Physiol. 2011;301(4):H1266–75.PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    van der Heijden OW, et al. Uterine artery remodeling and reproductive performance are impaired in endothelial nitric oxide synthase-deficient mice. Biol Reprod. 2005;72(5):1161–8.PubMedCrossRefGoogle Scholar
  30. 30.
    Crews JK, et al. Decreased endothelium-dependent vascular relaxation during reduction of uterine perfusion pressure in pregnant rat. Hypertension. 2000;35(1 Pt 2):367–72.PubMedCrossRefGoogle Scholar
  31. 31.
    Buhimschi I, et al. Involvement of a nitric oxide-cyclic guanosine monophosphate pathway in control of human uterine contractility during pregnancy. Am J Obstet Gynecol. 1995;172(5):1577–84.PubMedCrossRefGoogle Scholar
  32. 32.
    Goncalves-Rizzi VH, et al. Sodium nitrite attenuates hypertension-in-pregnancy and blunts increases in soluble fms-like tyrosine kinase-1 and in vascular endothelial growth factor. Nitric Oxide. 2016;57:71–8.PubMedCrossRefGoogle Scholar
  33. 33.
    Choi JW, Im MW, Pai SH. Nitric oxide production increases during normal pregnancy and decreases in preeclampsia. Ann Clin Lab Sci. 2002;32(3):257–63.PubMedGoogle Scholar
  34. 34.
    Seligman SP, et al. The role of nitric oxide in the pathogenesis of preeclampsia. Am J Obstet Gynecol. 1994;171(4):944–8.PubMedCrossRefGoogle Scholar
  35. 35.
    Silver RK, et al. Evaluation of nitric oxide as a mediator of severe preeclampsia. Am J Obstet Gynecol. 1996;175(4 Pt 1):1013–7.PubMedCrossRefGoogle Scholar
  36. 36.
    Pathak N, et al. Estimation of oxidative products of nitric oxide (nitrates, nitrites) in preeclampsia. Aust N Z J Obstet Gynaecol. 1999;39(4):484–7.PubMedCrossRefGoogle Scholar
  37. 37.
    Pimentel AM, et al. L-arginine-nitric oxide pathway and oxidative stress in plasma and platelets of patients with pre-eclampsia. Hypertens Res. 2013;36(9):783–8.PubMedCrossRefGoogle Scholar
  38. 38.
    Eleuterio NM, et al. Relationship between adiponectin and nitrite in healthy and preeclampsia pregnancies. Clin Chim Acta. 2013;423:112–5.PubMedCrossRefGoogle Scholar
  39. 39.
    • Sandrim VC, et al. Nitric oxide formation is inversely related to serum levels of antiangiogenic factors soluble fms-like tyrosine kinase-1 and soluble endogline in preeclampsia. Hypertension. 2008;52(2):402–7. Provides clinical evidence for impaired NO formation in PE or gestational hypertension, and makes a case for sFlt-1 and sEng inhibiting NO formation based on significant negative correlation between antiangiogenic factors and circulating nitrite concentrations. sThe r 2 values were on the order of 0.25 and 0.36 for sFlt-1 and sEng, respectively. PubMedCrossRefGoogle Scholar
  40. 40.
    Zeng Y, et al. Homocysteine, endothelin-1 and nitric oxide in patients with hypertensive disorders complicating pregnancy. Int J Clin Exp Pathol. 2015;8(11):15275–9.PubMedPubMedCentralGoogle Scholar
  41. 41.
    Pettersson A, Hedner T, Milsom I. Increased circulating concentrations of asymmetric dimethyl arginine (ADMA), an endogenous inhibitor of nitric oxide synthesis, in preeclampsia. Acta Obstet Gynecol Scand. 1998;77(8):808–13.PubMedCrossRefGoogle Scholar
  42. 42.
    Sankaralingam S, Xu H, Davidge ST. Arginase contributes to endothelial cell oxidative stress in response to plasma from women with preeclampsia. Cardiovasc Res. 2010;85(1):194–203.PubMedCrossRefGoogle Scholar
  43. 43.
    Bernardi FC, et al. Plasma nitric oxide, endothelin-1, arginase and superoxide dismutase in the plasma and placentae from preeclamptic patients. An Acad Bras Cienc. 2015;87(2):713–9.PubMedCrossRefGoogle Scholar
  44. 44.
    Rytlewski K, et al. Effects of prolonged oral supplementation with l-arginine on blood pressure and nitric oxide synthesis in preeclampsia. Eur J Clin Investig. 2005;35(1):32–7.CrossRefGoogle Scholar
  45. 45.
    Camarena Pulido EE, et al. Efficacy of L-arginine for preventing preeclampsia in high-risk pregnancies: a double-blind, randomized, clinical trial. Hypertens Pregnancy. 2016;35(2):217–25.PubMedCrossRefGoogle Scholar
  46. 46.
    Vadillo-Ortega F, et al. Effect of supplementation during pregnancy with L-arginine and antioxidant vitamins in medical food on pre-eclampsia in high risk population: randomised controlled trial. BMJ. 2011;342:d2901.PubMedPubMedCentralCrossRefGoogle Scholar
  47. 47.
    Khalil AA, et al. Asymmetric dimethylarginine, arginine and homoarginine at 11-13 weeks' gestation and preeclampsia: a case-control study. J Hum Hypertens. 2013;27(1):38–43.PubMedCrossRefGoogle Scholar
  48. 48.
    Lopez-Alarcon M, et al. Serial determinations of asymmetric dimethylarginine and homocysteine during pregnancy to predict pre-eclampsia: a longitudinal study. BJOG. 2015;122(12):1586–92.PubMedCrossRefGoogle Scholar
  49. 49.
    Zheng JJ, et al. Assessment of ADMA, estradiol, and progesterone in severe preeclampsia. Clin Exp Hypertens. 2016;38(4):347–51.PubMedCrossRefGoogle Scholar
  50. 50.
    Laskowska M, Laskowska K, Oleszczuk J. PP135. Maternal serum levels of endothelial nitric oxide synthase and ADMA, an endogenous ENOS inhibitor in pregnancies complicated by severe preeclampsia. Pregnancy Hypertens. 2012;2(3):312.PubMedGoogle Scholar
  51. 51.
    Vallance P, Leiper J. Cardiovascular biology of the asymmetric dimethylarginine:dimethylarginine dimethylaminohydrolase pathway. Arterioscler Thromb Vasc Biol. 2004;24(6):1023–30.PubMedCrossRefGoogle Scholar
  52. 52.
    Siroen MP, et al. The clinical significance of asymmetric dimethylarginine. Annu Rev Nutr. 2006;26:203–28.PubMedCrossRefGoogle Scholar
  53. 53.
    Bian Z, Shixia C, Duan T. First-trimester maternal serum levels of sFLT1, PGF and ADMA predict preeclampsia. PLoS One. 2015;10(4):e0124684.PubMedPubMedCentralCrossRefGoogle Scholar
  54. 54.
    Gumus E, et al. Possible role of asymmetric dimethylarginine (ADMA) in prediction of perinatal outcome in preeclampsia and fetal growth retardation related to preeclampsia. J Matern Fetal Neonatal Med. 2016;29(23):3806–11.PubMedCrossRefGoogle Scholar
  55. 55.
    Alpoim PN, et al. Assessment of L-arginine asymmetric 1 dimethyl (ADMA) in early-onset and late-onset (severe) preeclampsia. Nitric Oxide. 2013;33:81–2.PubMedCrossRefGoogle Scholar
  56. 56.
    Boger RH, et al. The role of nitric oxide synthase inhibition by asymmetric dimethylarginine in the pathophysiology of preeclampsia. Gynecol Obstet Investig. 2010;69(1):1–13.CrossRefGoogle Scholar
  57. 57.
    Anderssohn M, et al. Severely decreased activity of placental dimethylarginine dimethylaminohydrolase in pre-eclampsia. Eur J Obstet Gynecol Reprod Biol. 2012;161(2):152–6.PubMedCrossRefGoogle Scholar
  58. 58.
    Ehsanipoor RM, et al. Nitric oxide and carbon monoxide production and metabolism in preeclampsia. Reprod Sci. 2013;20(5):542–8.PubMedPubMedCentralCrossRefGoogle Scholar
  59. 59.
    Akbar F, et al. Haplotypic association of DDAH1 with susceptibility to pre-eclampsia. Mol Hum Reprod. 2005;11(1):73–7.PubMedCrossRefGoogle Scholar
  60. 60.
    Kromer W, et al. Direct comparison between the ulcer-healing effects of two H(+)-K(+)-ATPase inhibitors, one M1-selective antimuscarinic and one H2 receptor antagonist in the rat. Pharmacology. 1990;41(6):333–7.PubMedCrossRefGoogle Scholar
  61. 61.
    Maas R. Pharmacotherapies and their influence on asymmetric dimethylargine (ADMA). Vasc Med. 2005;10(Suppl 1):S49–57.PubMedCrossRefGoogle Scholar
  62. 62.
    • Vanhoutte PM, et al. Thirty years of saying NO: sources, fate, actions, and misfortunes of the endothelium-derived vasodilator mediator. Circ Res. 2016;119(2):375–96. A detailed, illustrated, tour-de-force review by one of the leading investigators in the field that covers NO signaling, mostly in normal rather than pathological conditions. Well-illustrated and comprehensive. PubMedCrossRefGoogle Scholar
  63. 63.
    Duckles SP, Miller VM. Hormonal modulation of endothelial NO production. Pflugers Arch. 2010;459(6):841–51.PubMedPubMedCentralCrossRefGoogle Scholar
  64. 64.
    Miller VM, Duckles SP. Vascular actions of estrogens: functional implications. Pharmacol Rev. 2008;60(2):210–41.PubMedPubMedCentralCrossRefGoogle Scholar
  65. 65.
    Meyer MR, et al. Non-genomic regulation of vascular cell function and growth by estrogen. Mol Cell Endocrinol. 2009;308(1–2):9–16.PubMedPubMedCentralCrossRefGoogle Scholar
  66. 66.
    Haas E, et al. Regulatory role of G protein-coupled estrogen receptor for vascular function and obesity. Circ Res. 2009;104(3):288–91.PubMedPubMedCentralCrossRefGoogle Scholar
  67. 67.
    Tropea T, et al. Pregnancy augments G protein estrogen receptor (GPER) induced Vasodilation in rat uterine arteries via the nitric oxide - cGMP signaling pathway. PLoS One. 2015;10(11):e0141997.PubMedPubMedCentralCrossRefGoogle Scholar
  68. 68.
    Lee DK, Nevo O. 2-Methoxyestradiol regulates VEGFR-2 and sFlt-1 expression in human placenta. Placenta. 2015;36(2):125–30.PubMedCrossRefGoogle Scholar
  69. 69.
    Shen Z, et al. Decreased maternal serum 2-methoxyestradiol levels are associated with the development of preeclampsia. Cell Physiol Biochem. 2014;34(6):2189–99.PubMedCrossRefGoogle Scholar
  70. 70.
    Berkane N, et al. From pregnancy to preeclampsia: a key role for estrogens. Endocr Rev. 2017;38(2):123–44.PubMedCrossRefGoogle Scholar
  71. 71.
    Jobe SO, Tyler CT, Magness RR. Aberrant synthesis, metabolism, and plasma accumulation of circulating estrogens and estrogen metabolites in preeclampsia implications for vascular dysfunction. Hypertension. 2013;61(2):480–7.PubMedPubMedCentralCrossRefGoogle Scholar
  72. 72.
    Fernandez AR, Omar SZ, Husain R. Role of Genistein in preeclampsia: a case-control study. J Reprod Med. 2016;61(1–2):47–51.PubMedGoogle Scholar
  73. 73.
    Ni Y, et al. Pregnancy augments uteroplacental vascular endothelial growth factor gene expression and vasodilator effects. Am J Phys. 1997;273(2 Pt 2):H938–44.Google Scholar
  74. 74.
    Ni Y, Meyer M, Osol G. Gestation increases nitric oxide-mediated vasodilation in rat uterine arteries. Am J Obstet Gynecol. 1997;176(4):856–64.PubMedCrossRefGoogle Scholar
  75. 75.
    Boeldt DS, et al. Positive versus negative effects of VEGF165 on Ca2+ signaling and NO production in human endothelial cells. Am J Physiol Heart Circ Physiol. 2017;312(1):H173–81.PubMedCrossRefGoogle Scholar
  76. 76.
    Ahmad S, Ahmed A. Elevated placental soluble vascular endothelial growth factor receptor-1 inhibits angiogenesis in preeclampsia. Circ Res. 2004;95(9):884–91.PubMedCrossRefGoogle Scholar
  77. 77.
    • Maynard SE, 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(5):649–58. A study that shored up the case for the importance of sFlt-1 in PE, and led to an interesting essay in the New Yorker (The Preeclampsia Puzzle) that described the medical, scientific and human background of this discovery. Available for free on the web ( http://www.newyorker.com/magazine/2006/07/24/the- preeclampsia-puzzle). PubMedPubMedCentralCrossRefGoogle Scholar
  78. 78.
    Maynard S, Epstein FH, Karumanchi SA. Preeclampsia and angiogenic imbalance. Annu Rev Med. 2008;59:61–78.PubMedCrossRefGoogle Scholar
  79. 79.
    Mangos GJ, et al. Markers of cardiovascular disease risk after hypertension in pregnancy. J Hypertens. 2012;30(2):351–8.PubMedCrossRefGoogle Scholar
  80. 80.
    Lommerse T, et al. Endothelium-dependent vasodilatation in formerly preeclamptic women correlates inversely with body mass index and varies independently of plasma volume. Reprod Sci. 2007;14(8):765–70.PubMedCrossRefGoogle Scholar
  81. 81.
    Germain AM, et al. Endothelial dysfunction: a link among preeclampsia, recurrent pregnancy loss, and future cardiovascular events? Hypertension. 2007;49(1):90–5.PubMedCrossRefGoogle Scholar
  82. 82.
    Chambers JC, et al. Association of maternal endothelial dysfunction with preeclampsia. JAMA. 2001;285(12):1607–12.PubMedCrossRefGoogle Scholar
  83. 83.
    Hamad RR, et al. Impaired endothelial function and elevated levels of pentraxin 3 in early-onset preeclampsia. Acta Obstet Gynecol Scand. 2012;91(1):50–6.PubMedCrossRefGoogle Scholar
  84. 84.
    Paez O, et al. Parallel decrease in arterial distensibility and in endothelium-dependent dilatation in young women with a history of pre-eclampsia. Clin Exp Hypertens. 2009;31(7):544–52.PubMedCrossRefGoogle Scholar
  85. 85.
    Goynumer G, et al. Vascular risk in women with a history of severe preeclampsia. J Clin Ultrasound. 2013;41(3):145–50.PubMedCrossRefGoogle Scholar
  86. 86.
    Yinon Y, et al. Vascular dysfunction in women with a history of preeclampsia and intrauterine growth restriction: insights into future vascular risk. Circulation. 2010;122(18):1846–53.PubMedCrossRefGoogle Scholar
  87. 87.
    Weissgerber TL, et al. Impaired flow-mediated dilation before, during, and after preeclampsia: a systematic review and meta-analysis. Hypertension. 2016;67(2):415–23.PubMedGoogle Scholar
  88. 88.
    • Kublickiene KR, et al. Preeclampsia: evidence for impaired shear stress-mediated nitric oxide release in uterine circulation. Am J Obstet Gynecol. 2000;183(1):160–6. A study on isolated subcutaneous arteries from women who had a normal vs. PE pregnancy that identifies loss of shear stress-induced NO vasodilation. This illustrates a selective ‘lesion’ in PE (since acetylcholine-induced endothelial responses were normal) and the fact that it is still present several years after a PE pregnancy. PubMedCrossRefGoogle Scholar
  89. 89.
    Nelson SH, et al. Pregnancy augments nitric oxide-dependent dilator response to acetylcholine in the human uterine artery. Hum Reprod. 1998;13(5):1361–7.PubMedCrossRefGoogle Scholar
  90. 90.
    Nelson SH, et al. Increased nitric oxide synthase activity and expression in the human uterine artery during pregnancy. Circ Res. 2000;87(5):406–11.PubMedCrossRefGoogle Scholar
  91. 91.
    Morschauser TJ, et al. Local effects of pregnancy on connexin proteins that mediate Ca2+- associated uterine endothelial NO synthesis. Hypertension. 2014;63(3):589–94.PubMedCrossRefGoogle Scholar
  92. 92.
    Joyce JM, et al. Endothelial vasodilator production by uterine and systemic arteries. IX. eNOS gradients in cycling and pregnant ewes. Am J Physiol Heart Circ Physiol. 2002;282(1):H342–8.PubMedCrossRefGoogle Scholar
  93. 93.
    Laskowska M, Laskowska K, Oleszczuk J. The relation of maternal serum eNOS, NOSTRIN and ADMA levels with aetiopathogenesis of preeclampsia and/or intrauterine fetal growth restriction. J Matern Fetal Neonatal Med. 2015;28(1):26–32.PubMedCrossRefGoogle Scholar
  94. 94.
    Laskowska M, et al. A comparison of maternal serum levels of endothelial nitric oxide synthase, asymmetric dimethylarginine, and homocysteine in normal and preeclamptic pregnancies. Med Sci Monit. 2013;19:430–7.PubMedPubMedCentralCrossRefGoogle Scholar
  95. 95.
    Aleman I, et al. Endothelial and inducible nitric oxide synthase expression in Venezuelan patients with pre-eclampsia. Investig Clin. 2008;49(3):321–30.Google Scholar
  96. 96.
    Mazzanti L, et al. Nitric oxide and peroxynitrite platelet levels in gestational hypertension and preeclampsia. Platelets. 2012;23(1):26–35.PubMedCrossRefGoogle Scholar
  97. 97.
    Ramadoss J, Pastore MB, Magness RR. Endothelial caveolar subcellular domain regulation of endothelial nitric oxide synthase. Clin Exp Pharmacol Physiol. 2013;40(11):753–64.PubMedPubMedCentralCrossRefGoogle Scholar
  98. 98.
    Smith-Jackson K, et al. Placental expression of eNOS, iNOS and the major protein components of caveolae in women with pre-eclampsia. Placenta. 2015;36(5):607–10.PubMedCrossRefGoogle Scholar
  99. 99.
    Myatt L, et al. Endothelial nitric oxide synthase in placental villous tissue from normal, pre-eclamptic and intrauterine growth restricted pregnancies. Hum Reprod. 1997;12(1):167–72.PubMedCrossRefGoogle Scholar
  100. 100.
    Kim YJ, et al. Reduced L-arginine level and decreased placental eNOS activity in preeclampsia. Placenta. 2006;27(4–5):438–44.PubMedCrossRefGoogle Scholar
  101. 101.
    Orange SJ, et al. Placental endothelial nitric oxide synthase localization and expression in normal human pregnancy and pre-eclampsia. Clin Exp Pharmacol Physiol. 2003;30(5–6):376–81.PubMedCrossRefGoogle Scholar
  102. 102.
    Motta-Mejia C, et al. Placental vesicles carry active endothelial nitric oxide Synthase and their activity is reduced in preeclampsia. Hypertension. 2017;70(2):372–81.PubMedPubMedCentralCrossRefGoogle Scholar
  103. 103.
    Maria Procopciuc L. et al., Maternal/fetal eNOS-Glu298Asp genotypes and their influence on the severity, prognosis, and lipid profile of preeclampsia. J Matern Fetal Neonatal Med 2017: p. 1–8.Google Scholar
  104. 104.
    Sakar MN, et al. Association of endothelial nitric oxide synthase gene G894T polymorphism and serum nitric oxide levels in patients with preeclampsia and gestational hypertension. J Matern Fetal Neonatal Med. 2015;28(16):1907–11.PubMedCrossRefGoogle Scholar
  105. 105.
    Alpoim PN, et al. Polymorphisms in endothelial nitric oxide synthase gene in early and late severe preeclampsia. Nitric Oxide. 2014;42:19–23.PubMedCrossRefGoogle Scholar
  106. 106.
    Chen Y, et al. Polymorphisms of the endothelial nitric oxide synthase gene in preeclampsia in a Han Chinese population. Gynecol Obstet Investig. 2014;77(3):150–5.CrossRefGoogle Scholar
  107. 107.
    Rahimi Z, Aghaei A, Vaisi-Raygani A. Endothelial nitric oxide Synthase (eNOS) 4a/b and G894T polymorphisms and susceptibility to preeclampsia. J Reprod Infertil. 2013;14(4):184–9.PubMedPubMedCentralGoogle Scholar
  108. 108.
    Dai B, et al. The polymorphism for endothelial nitric oxide synthase gene, the level of nitric oxide and the risk for pre-eclampsia: a meta-analysis. Gene. 2013;519(1):187–93.PubMedCrossRefGoogle Scholar
  109. 109.
    Tulenko T, et al. The in vitro effect on arterial wall function of serum from patients with pregnancy-induced hypertension. Am J Obstet Gynecol. 1987;156(4):817–23.PubMedCrossRefGoogle Scholar
  110. 110.
    Li F, et al. eNOS deficiency acts through endothelin to aggravate sFlt-1-induced pre-eclampsia-like phenotype. J Am Soc Nephrol. 2012;23(4):652–60.PubMedPubMedCentralCrossRefGoogle Scholar
  111. 111.
    Zhu M, et al. Restoring placental growth factor-soluble fms-like tyrosine kinase-1 balance reverses vascular hyper-reactivity and hypertension in pregnancy. Am J Physiol Regul Integr Comp Physiol. 2016;311(3):R505–21.PubMedPubMedCentralCrossRefGoogle Scholar
  112. 112.
    Haram K, Mortensen JH, Nagy B. Genetic aspects of preeclampsia and the HELLP syndrome. J Pregnancy. 2014;2014:910751.PubMedPubMedCentralCrossRefGoogle Scholar
  113. 113.
    • Berends AL, et al. STOX1 Gene in pre-eclampsia and intrauterine growth restriction. BJOG. 2007;114(9):1163–7. First study implicating the STOX gene as a hereditary basis for PE. PubMedCrossRefGoogle Scholar
  114. 114.
    Rigourd V, et al. Re-evaluation of the role of STOX1 transcription factor in placental development and preeclampsia. J Reprod Immunol. 2009;82(2):174–81.PubMedCrossRefGoogle Scholar
  115. 115.
    Kukor Z, Valent S, Toth M. Regulation of nitric oxide synthase activity by tetrahydrobiopterin in human placentae from normal and pre-eclamptic pregnancies. Placenta. 2000;21(8):763–72.PubMedCrossRefGoogle Scholar
  116. 116.
    • Sankaralingam S, et al. Evidence for increased methylglyoxal in the vasculature of women with preeclampsia: role in upregulation of LOX-1 and arginase. Hypertension. 2009;54(4):897–904. Identifies a mechanism in which methylglyoxal increases arginase, and then LOX-1 expression in cultured endothelial cells, likely via uncoupling of eNOS. This is important since LOX-1 and arginase both contribute to oxidative stress, and are increased in PE. PubMedCrossRefGoogle Scholar
  117. 117.
    Cominacini L, et al. The binding of oxidized low density lipoprotein (ox-LDL) to ox-LDL receptor-1 reduces the intracellular concentration of nitric oxide in endothelial cells through an increased production of superoxide. J Biol Chem. 2001;276(17):13750–5.PubMedCrossRefGoogle Scholar
  118. 118.
    • Ahmed A, Ramma W. Unravelling the theories of pre-eclampsia: are the protective pathways the new paradigm? Br J Pharmacol. 2015;172(6):1574–86. A provocative review paper by the person who first proposed a role for sFlt-1 and reduced VEGF signaling in PE (in 1997). PubMedPubMedCentralCrossRefGoogle Scholar
  119. 119.
    Ozler A, et al. Serum levels of neopterin, tumor necrosis factor-alpha and Interleukin-6 in preeclampsia: relationship with disease severity. Eur Rev Med Pharmacol Sci. 2012;16(12):1707–12.PubMedGoogle Scholar
  120. 120.
    Kronborg CS, et al. Longitudinal measurement of cytokines in pre-eclamptic and normotensive pregnancies. Acta Obstet Gynecol Scand. 2011;90(7):791–6.PubMedCrossRefGoogle Scholar
  121. 121.
    Nayeri UA, et al. Antenatal corticosteroids impact the inflammatory rather than the antiangiogenic profile of women with preeclampsia. Hypertension. 2014;63(6):1285–92.PubMedCrossRefGoogle Scholar
  122. 122.
    Harmon AC, et al. The role of inflammation in the pathology of preeclampsia. Clin Sci. 2016;130(6):409–19.PubMedPubMedCentralCrossRefGoogle Scholar
  123. 123.
    Saleh L, et al. The emerging role of endothelin-1 in the pathogenesis of pre-eclampsia. Ther Adv Cardiovasc Dis. 2016;10(5):282–93.PubMedCrossRefGoogle Scholar
  124. 124.
    Lankhorst S, Danser AH, van den Meiracker AH. Endothelin-1 and antiangiogenesis. Am J Physiol Regul Integr Comp Physiol. 2016;310(3):R230–4.PubMedCrossRefGoogle Scholar
  125. 125.
    Jain A. Endothelin-1: a key pathological factor in pre-eclampsia? Reprod BioMed Online. 2012;25(5):443–9.PubMedCrossRefGoogle Scholar
  126. 126.
    George EM, Granger JP. Endothelin: key mediator of hypertension in preeclampsia. Am J Hypertens. 2011;24(9):964–9.PubMedPubMedCentralCrossRefGoogle Scholar
  127. 127.
    • Bourque SL, Davidge ST, Adams MA. The interaction between endothelin-1 and nitric oxide in the vasculature: new perspectives. Am J Physiol Regul Integr Comp Physiol. 2011;300(6):R1288–95. A review that explains the big endothelin -NO story well, and provides a perspective on the potential importance of this physiological pathway under normal conditions vs. those of diminished NO bioavailability (such as PE). PubMedCrossRefGoogle Scholar
  128. 128.
    Conrad KP. Emerging role of relaxin in the maternal adaptations to normal pregnancy: implications for preeclampsia. Semin Nephrol. 2011;31(1):15–32.PubMedPubMedCentralCrossRefGoogle Scholar
  129. 129.
    Bakrania B, et al. The Endothelin type a receptor as a potential therapeutic target in preeclampsia. Int J Mol Sci. 2017;18(3):E522.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2017

Authors and Affiliations

  1. 1.Department of Obstetrics, Gynecology and Reproductive SciencesUniversity of Vermont College of MedicineBurlingtonUSA
  2. 2.Department of Biology, Ecology and Earth ScienceUniversity of CalabriaCosenzaItaly

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