Official reprint from UpToDate®
www.uptodate.com ©2017 UpToDate®

Preeclampsia: Pathogenesis

S Ananth Karumanchi, MD
Kee-Hak Lim, MD
Phyllis August, MD, MPH
Section Editor
Susan M Ramin, MD
Deputy Editor
Vanessa A Barss, MD, FACOG


Preeclampsia is a syndrome characterized by the onset of hypertension and either proteinuria or end-organ dysfunction after 20 weeks of gestation (table 1). Additional signs and symptoms that can occur include visual disturbances, headache, epigastric pain, thrombocytopenia, and abnormal liver function. These clinical manifestations result from mild to severe microangiopathy of target organs, including the brain, liver, kidney, and placenta [1]. Potential maternal sequelae include pulmonary edema, cerebral hemorrhage, hepatic failure, renal failure, and death. The fetal/neonatal burden of disease results from placental hypoperfusion and the frequent need for preterm delivery.

The pathophysiology of preeclampsia likely involves both maternal and fetal/placental factors. Abnormalities in the development of placental vasculature early in pregnancy may result in relative placental underperfusion/hypoxia/ischemia, which then leads to release of antiangiogenic factors into the maternal circulation that alter maternal systemic endothelial function and cause hypertension and other manifestations of the disease. However, the molecular basis for abnormal placental development and placental dysregulation of these pathogenic factors remains unknown. The role of angiogenic proteins in early placental vascular development are under investigation.

Our current understanding of mechanisms causing the pathologic changes observed in preeclampsia will be reviewed here. The clinical features and management of preeclampsia, and treatment of hypertension during pregnancy are discussed separately. (See "Preeclampsia: Clinical features and diagnosis" and "Preeclampsia: Management and prognosis" and "Management of hypertension in pregnant and postpartum women".)


The critical role of the placenta in the pathophysiology of preeclampsia is supported by epidemiologic and experimental data that show:

Placental tissue is necessary for development of the disease, but the fetus is not [2-4]


Subscribers log in here

To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information or to purchase a personal subscription, click below on the option that best describes you:
Literature review current through: Dec 2016. | This topic last updated: Tue Jan 17 00:00:00 GMT+00:00 2017.
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2017 UpToDate, Inc.
  1. Lain KY, Roberts JM. Contemporary concepts of the pathogenesis and management of preeclampsia. JAMA 2002; 287:3183.
  2. Moore-Maxwell CA, Robboy SJ. Placental site trophoblastic tumor arising from antecedent molar pregnancy. Gynecol Oncol 2004; 92:708.
  3. Nugent CE, Punch MR, Barr M Jr, et al. Persistence of partial molar placenta and severe preeclampsia after selective termination in a twin pregnancy. Obstet Gynecol 1996; 87:829.
  4. Matsuo K, Kooshesh S, Dinc M, et al. Late postpartum eclampsia: report of two cases managed by uterine curettage and review of the literature. Am J Perinatol 2007; 24:257.
  5. Kaufmann P, Black S, Huppertz B. Endovascular trophoblast invasion: implications for the pathogenesis of intrauterine growth retardation and preeclampsia. Biol Reprod 2003; 69:1.
  6. Pijnenborg R, Vercruysse L, Hanssens M. The uterine spiral arteries in human pregnancy: facts and controversies. Placenta 2006; 27:939.
  7. Zhou Y, Damsky CH, Fisher SJ. Preeclampsia is associated with failure of human cytotrophoblasts to mimic a vascular adhesion phenotype. One cause of defective endovascular invasion in this syndrome? J Clin Invest 1997; 99:2152.
  8. Zhou Y, Damsky CH, Chiu K, et al. Preeclampsia is associated with abnormal expression of adhesion molecules by invasive cytotrophoblasts. J Clin Invest 1993; 91:950.
  9. Roberts JM, Redman CW. Pre-eclampsia: more than pregnancy-induced hypertension. Lancet 1993; 341:1447.
  10. Meekins JW, Pijnenborg R, Hanssens M, et al. A study of placental bed spiral arteries and trophoblast invasion in normal and severe pre-eclamptic pregnancies. Br J Obstet Gynaecol 1994; 101:669.
  11. Brosens I, Pijnenborg R, Vercruysse L, Romero R. The "Great Obstetrical Syndromes" are associated with disorders of deep placentation. Am J Obstet Gynecol 2011; 204:193.
  12. Ilekis JV, Reddy UM, Roberts JM. Preeclampsia--a pressing problem: an executive summary of a National Institute of Child Health and Human Development workshop. Reprod Sci 2007; 14:508.
  13. Huppertz B. Placental origins of preeclampsia: challenging the current hypothesis. Hypertension 2008; 51:970.
  14. Cross JC, Werb Z, Fisher SJ. Implantation and the placenta: key pieces of the development puzzle. Science 1994; 266:1508.
  15. Lim KH, Zhou Y, Janatpour M, et al. Human cytotrophoblast differentiation/invasion is abnormal in pre-eclampsia. Am J Pathol 1997; 151:1809.
  16. Zhou Y, Gormley MJ, Hunkapiller NM, et al. Reversal of gene dysregulation in cultured cytotrophoblasts reveals possible causes of preeclampsia. J Clin Invest 2013; 123:2862.
  17. Casper FW, Seufert RJ. Atrial natriuretic peptide (ANP) in preeclampsia-like syndrome in a rat model. Exp Clin Endocrinol Diabetes 1995; 103:292.
  18. Makris A, Thornton C, Thompson J, et al. Uteroplacental ischemia results in proteinuric hypertension and elevated sFLT-1. Kidney Int 2007; 71:977.
  19. Dekker GA. Risk factors for preeclampsia. Clin Obstet Gynecol 1999; 42:422.
  20. Palmer SK, Moore LG, Young D, et al. Altered blood pressure course during normal pregnancy and increased preeclampsia at high altitude (3100 meters) in Colorado. Am J Obstet Gynecol 1999; 180:1161.
  21. Robertson WB, Brosens I, Dixon HG. The pathological response of the vessels of the placental bed to hypertensive pregnancy. J Pathol Bacteriol 1967; 93:581.
  22. Gerretsen G, Huisjes HJ, Elema JD. Morphological changes of the spiral arteries in the placental bed in relation to pre-eclampsia and fetal growth retardation. Br J Obstet Gynaecol 1981; 88:876.
  23. Brosens IA, Robertson WB, Dixon HG. The role of the spiral arteries in the pathogenesis of preeclampsia. Obstet Gynecol Annu 1972; 1:177.
  24. Khong TY, De Wolf F, Robertson WB, Brosens I. Inadequate maternal vascular response to placentation in pregnancies complicated by pre-eclampsia and by small-for-gestational age infants. Br J Obstet Gynaecol 1986; 93:1049.
  25. De Wolf F, Robertson WB, Brosens I. The ultrastructure of acute atherosis in hypertensive pregnancy. Am J Obstet Gynecol 1975; 123:164.
  26. Salafia CM, Pezzullo JC, Ghidini A, et al. Clinical correlations of patterns of placental pathology in preterm pre-eclampsia. Placenta 1998; 19:67.
  27. Walker JJ. Pre-eclampsia. Lancet 2000; 356:1260.
  28. Wang X, Athayde N, Trudinger B. A proinflammatory cytokine response is present in the fetal placental vasculature in placental insufficiency. Am J Obstet Gynecol 2003; 189:1445.
  29. Redman CW, Sargent IL. Preeclampsia and the systemic inflammatory response. Semin Nephrol 2004; 24:565.
  30. Roberts JM, Speer P. Antioxidant therapy to prevent preeclampsia. Semin Nephrol 2004; 24:557.
  31. Yinon Y, Nevo O, Xu J, et al. Severe intrauterine growth restriction pregnancies have increased placental endoglin levels: hypoxic regulation via transforming growth factor-beta 3. Am J Pathol 2008; 172:77.
  32. Rusterholz C, Hahn S, Holzgreve W. Role of placentally produced inflammatory and regulatory cytokines in pregnancy and the etiology of preeclampsia. Semin Immunopathol 2007; 29:151.
  33. Maynard S, Epstein FH, Karumanchi SA. Preeclampsia and angiogenic imbalance. Annu Rev Med 2008; 59:61.
  34. Robillard PY, Hulsey TC, Périanin J, et al. Association of pregnancy-induced hypertension with duration of sexual cohabitation before conception. Lancet 1994; 344:973.
  35. Koelman CA, Coumans AB, Nijman HW, et al. Correlation between oral sex and a low incidence of preeclampsia: a role for soluble HLA in seminal fluid? J Reprod Immunol 2000; 46:155.
  36. Wang JX, Knottnerus AM, Schuit G, et al. Surgically obtained sperm, and risk of gestational hypertension and pre-eclampsia. Lancet 2002; 359:673.
  37. Einarsson JI, Sangi-Haghpeykar H, Gardner MO. Sperm exposure and development of preeclampsia. Am J Obstet Gynecol 2003; 188:1241.
  38. Smith GN, Walker M, Tessier JL, Millar KG. Increased incidence of preeclampsia in women conceiving by intrauterine insemination with donor versus partner sperm for treatment of primary infertility. Am J Obstet Gynecol 1997; 177:455.
  39. Klonoff-Cohen HS, Savitz DA, Cefalo RC, McCann MF. An epidemiologic study of contraception and preeclampsia. JAMA 1989; 262:3143.
  40. Mills JL, Klebanoff MA, Graubard BI, et al. Barrier contraceptive methods and preeclampsia. JAMA 1991; 265:70.
  41. Masoudian P, Nasr A, de Nanassy J, et al. Oocyte donation pregnancies and the risk of preeclampsia or gestational hypertension: a systematic review and metaanalysis. Am J Obstet Gynecol 2016; 214:328.
  42. Gleicher N. Why much of the pathophysiology of preeclampsia-eclampsia must be of an autoimmune nature. Am J Obstet Gynecol 2007; 196:5.e1.
  43. Loke YW, King A. Immunology of implantation. Baillieres Best Pract Res Clin Obstet Gynaecol 2000; 14:827.
  44. Huang SJ, Chen CP, Schatz F, et al. Pre-eclampsia is associated with dendritic cell recruitment into the uterine decidua. J Pathol 2008; 214:328.
  45. Hiby SE, Walker JJ, O'shaughnessy KM, et al. Combinations of maternal KIR and fetal HLA-C genes influence the risk of preeclampsia and reproductive success. J Exp Med 2004; 200:957.
  46. Saftlas AF, Beydoun H, Triche E. Immunogenetic determinants of preeclampsia and related pregnancy disorders: a systematic review. Obstet Gynecol 2005; 106:162.
  47. Xia Y, Wen H, Bobst S, et al. Maternal autoantibodies from preeclamptic patients activate angiotensin receptors on human trophoblast cells. J Soc Gynecol Investig 2003; 10:82.
  48. Dechend R, Müller DN, Wallukat G, et al. AT1 receptor agonistic antibodies, hypertension, and preeclampsia. Semin Nephrol 2004; 24:571.
  49. Dechend R, Homuth V, Wallukat G, et al. AT(1) receptor agonistic antibodies from preeclamptic patients cause vascular cells to express tissue factor. Circulation 2000; 101:2382.
  50. Thway TM, Shlykov SG, Day MC, et al. Antibodies from preeclamptic patients stimulate increased intracellular Ca2+ mobilization through angiotensin receptor activation. Circulation 2004; 110:1612.
  51. Zhou CC, Ahmad S, Mi T, et al. Autoantibody from women with preeclampsia induces soluble Fms-like tyrosine kinase-1 production via angiotensin type 1 receptor and calcineurin/nuclear factor of activated T-cells signaling. Hypertension 2008; 51:1010.
  52. Granger JP, Alexander BT, Bennett WA, Khalil RA. Pathophysiology of pregnancy-induced hypertension. Am J Hypertens 2001; 14:178S.
  53. AbdAlla S, Lother H, el Massiery A, Quitterer U. Increased AT(1) receptor heterodimers in preeclampsia mediate enhanced angiotensin II responsiveness. Nat Med 2001; 7:1003.
  54. Zhou CC, Zhang Y, Irani RA, et al. Angiotensin receptor agonistic autoantibodies induce pre-eclampsia in pregnant mice. Nat Med 2008; 14:855.
  55. Wenzel K, Rajakumar A, Haase H, et al. Angiotensin II type 1 receptor antibodies and increased angiotensin II sensitivity in pregnant rats. Hypertension 2011; 58:77.
  56. Lachmeijer AM, Dekker GA, Pals G, et al. Searching for preeclampsia genes: the current position. Eur J Obstet Gynecol Reprod Biol 2002; 105:94.
  57. Mogren I, Högberg U, Winkvist A, Stenlund H. Familial occurrence of preeclampsia. Epidemiology 1999; 10:518.
  58. Cincotta RB, Brennecke SP. Family history of pre-eclampsia as a predictor for pre-eclampsia in primigravidas. Int J Gynaecol Obstet 1998; 60:23.
  59. Esplin MS, Fausett MB, Fraser A, et al. Paternal and maternal components of the predisposition to preeclampsia. N Engl J Med 2001; 344:867.
  60. Lie RT, Rasmussen S, Brunborg H, et al. Fetal and maternal contributions to risk of pre-eclampsia: population based study. BMJ 1998; 316:1343.
  61. Arngrímsson R, Sigurõardóttir S, Frigge ML, et al. A genome-wide scan reveals a maternal susceptibility locus for pre-eclampsia on chromosome 2p13. Hum Mol Genet 1999; 8:1799.
  62. Moses EK, Lade JA, Guo G, et al. A genome scan in families from Australia and New Zealand confirms the presence of a maternal susceptibility locus for pre-eclampsia, on chromosome 2. Am J Hum Genet 2000; 67:1581.
  63. Lachmeijer AM, Arngrímsson R, Bastiaans EJ, et al. A genome-wide scan for preeclampsia in the Netherlands. Eur J Hum Genet 2001; 9:758.
  64. Cnattingius S, Reilly M, Pawitan Y, Lichtenstein P. Maternal and fetal genetic factors account for most of familial aggregation of preeclampsia: a population-based Swedish cohort study. Am J Med Genet A 2004; 130A:365.
  65. Skjaerven R, Vatten LJ, Wilcox AJ, et al. Recurrence of pre-eclampsia across generations: exploring fetal and maternal genetic components in a population based cohort. BMJ 2005; 331:877.
  66. Carr DB, Epplein M, Johnson CO, et al. A sister's risk: family history as a predictor of preeclampsia. Am J Obstet Gynecol 2005; 193:965.
  67. van Dijk M, Mulders J, Poutsma A, et al. Maternal segregation of the Dutch preeclampsia locus at 10q22 with a new member of the winged helix gene family. Nat Genet 2005; 37:514.
  68. Duckitt K, Harrington D. Risk factors for pre-eclampsia at antenatal booking: systematic review of controlled studies. BMJ 2005; 330:565.
  69. Treloar SA, Cooper DW, Brennecke SP, et al. An Australian twin study of the genetic basis of preeclampsia and eclampsia. Am J Obstet Gynecol 2001; 184:374.
  70. Tuohy JF, James DK. Pre-eclampsia and trisomy 13. Br J Obstet Gynaecol 1992; 99:891.
  71. Bdolah Y, Palomaki GE, Yaron Y, et al. Circulating angiogenic proteins in trisomy 13. Am J Obstet Gynecol 2006; 194:239.
  72. van Dijk M, Thulluru HK, Mulders J, et al. HELLP babies link a novel lincRNA to the trophoblast cell cycle. J Clin Invest 2012; 122:4003.
  73. Johnson MP, Brennecke SP, East CE, et al. Genome-wide association scan identifies a risk locus for preeclampsia on 2q14, near the inhibin, beta B gene. PLoS One 2012; 7:e33666.
  74. Laasanen J, Hiltunen M, Romppanen EL, et al. Microsatellite marker association at chromosome region 2p13 in Finnish patients with preeclampsia and obstetric cholestasis suggests a common risk locus. Eur J Hum Genet 2003; 11:232.
  75. Laivuori H, Lahermo P, Ollikainen V, et al. Susceptibility loci for preeclampsia on chromosomes 2p25 and 9p13 in Finnish families. Am J Hum Genet 2003; 72:168.
  76. Paré E, Parry S, McElrath TF, et al. Clinical risk factors for preeclampsia in the 21st century. Obstet Gynecol 2014; 124:763.
  77. Zera CA, Seely EW, Wilkins-Haug LE, et al. The association of body mass index with serum angiogenic markers in normal and abnormal pregnancies. Am J Obstet Gynecol 2014; 211:247.e1.
  78. Redman CW, Sacks GP, Sargent IL. Preeclampsia: an excessive maternal inflammatory response to pregnancy. Am J Obstet Gynecol 1999; 180:499.
  79. Roberts JM, Taylor RN, Goldfien A. Clinical and biochemical evidence of endothelial cell dysfunction in the pregnancy syndrome preeclampsia. Am J Hypertens 1991; 4:700.
  80. Friedman SA, Schiff E, Emeis JJ, et al. Biochemical corroboration of endothelial involvement in severe preeclampsia. Am J Obstet Gynecol 1995; 172:202.
  81. Hsu CD, Iriye B, Johnson TR, et al. Elevated circulating thrombomodulin in severe preeclampsia. Am J Obstet Gynecol 1993; 169:148.
  82. Taylor RN, Crombleholme WR, Friedman SA, et al. High plasma cellular fibronectin levels correlate with biochemical and clinical features of preeclampsia but cannot be attributed to hypertension alone. Am J Obstet Gynecol 1991; 165:895.
  83. McCarthy AL, Woolfson RG, Raju SK, Poston L. Abnormal endothelial cell function of resistance arteries from women with preeclampsia. Am J Obstet Gynecol 1993; 168:1323.
  84. Cockell AP, Poston L. Flow-mediated vasodilatation is enhanced in normal pregnancy but reduced in preeclampsia. Hypertension 1997; 30:247.
  85. Pascoal IF, Lindheimer MD, Nalbantian-Brandt C, Umans JG. Preeclampsia selectively impairs endothelium-dependent relaxation and leads to oscillatory activity in small omental arteries. J Clin Invest 1998; 101:464.
  86. Roberts JM, Edep ME, Goldfien A, Taylor RN. Sera from preeclamptic women specifically activate human umbilical vein endothelial cells in vitro: morphological and biochemical evidence. Am J Reprod Immunol 1992; 27:101.
  87. Chambers JC, Fusi L, Malik IS, et al. Association of maternal endothelial dysfunction with preeclampsia. JAMA 2001; 285:1607.
  88. Levine RJ, Qian C, Maynard SE, et al. Serum sFlt1 concentration during preeclampsia and mid trimester blood pressure in healthy nulliparous women. Am J Obstet Gynecol 2006; 194:1034.
  89. Harskamp RE, Zeeman GG. Preeclampsia: at risk for remote cardiovascular disease. Am J Med Sci 2007; 334:291.
  90. Bellamy L, Casas JP, Hingorani AD, Williams DJ. Pre-eclampsia and risk of cardiovascular disease and cancer in later life: systematic review and meta-analysis. BMJ 2007; 335:974.
  91. Vikse BE, Irgens LM, Leivestad T, et al. Preeclampsia and the risk of end-stage renal disease. N Engl J Med 2008; 359:800.
  92. Levine RJ, Vatten LJ, Horowitz GL, et al. Pre-eclampsia, soluble fms-like tyrosine kinase 1, and the risk of reduced thyroid function: nested case-control and population based study. BMJ 2009; 339:b4336.
  93. Dvorak HF. Vascular permeability factor/vascular endothelial growth factor: a critical cytokine in tumor angiogenesis and a potential target for diagnosis and therapy. J Clin Oncol 2002; 20:4368.
  94. Ferrara N, Davis-Smyth T. The biology of vascular endothelial growth factor. Endocr Rev 1997; 18:4.
  95. 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.
  96. Zhou Y, McMaster M, Woo K, et al. Vascular endothelial growth factor ligands and receptors that regulate human cytotrophoblast survival are dysregulated in severe preeclampsia and hemolysis, elevated liver enzymes, and low platelets syndrome. Am J Pathol 2002; 160:1405.
  97. Vuorela P, Helske S, Hornig C, et al. Amniotic fluid--soluble vascular endothelial growth factor receptor-1 in preeclampsia. Obstet Gynecol 2000; 95:353.
  98. Koga K, Osuga Y, Yoshino O, et al. Elevated serum soluble vascular endothelial growth factor receptor 1 (sVEGFR-1) levels in women with preeclampsia. J Clin Endocrinol Metab 2003; 88:2348.
  99. Chaiworapongsa T, Romero R, Espinoza J, et al. Evidence supporting a role for blockade of the vascular endothelial growth factor system in the pathophysiology of preeclampsia. Young Investigator Award. Am J Obstet Gynecol 2004; 190:1541.
  100. McKeeman GC, Ardill JE, Caldwell CM, et al. Soluble vascular endothelial growth factor receptor-1 (sFlt-1) is increased throughout gestation in patients who have preeclampsia develop. Am J Obstet Gynecol 2004; 191:1240.
  101. Eremina V, Sood M, Haigh J, et al. Glomerular-specific alterations of VEGF-A expression lead to distinct congenital and acquired renal diseases. J Clin Invest 2003; 111:707.
  102. Levine RJ, Maynard SE, Qian C, et al. Circulating angiogenic factors and the risk of preeclampsia. N Engl J Med 2004; 350:672.
  103. Tsatsaris V, Goffin F, Munaut C, et al. Overexpression of the soluble vascular endothelial growth factor receptor in preeclamptic patients: pathophysiological consequences. J Clin Endocrinol Metab 2003; 88:5555.
  104. Ahmad S, Ahmed A. Elevated placental soluble vascular endothelial growth factor receptor-1 inhibits angiogenesis in preeclampsia. Circ Res 2004; 95:884.
  105. Taylor RN, Grimwood J, Taylor RS, et al. Longitudinal serum concentrations of placental growth factor: evidence for abnormal placental angiogenesis in pathologic pregnancies. Am J Obstet Gynecol 2003; 188:177.
  106. Tjoa ML, van Vugt JM, Mulders MA, et al. Plasma placenta growth factor levels in midtrimester pregnancies. Obstet Gynecol 2001; 98:600.
  107. Su YN, Lee CN, Cheng WF, et al. Decreased maternal serum placenta growth factor in early second trimester and preeclampsia. Obstet Gynecol 2001; 97:898.
  108. Tidwell SC, Ho HN, Chiu WH, et al. Low maternal serum levels of placenta growth factor as an antecedent of clinical preeclampsia. Am J Obstet Gynecol 2001; 184:1267.
  109. Polliotti BM, Fry AG, Saller DN, et al. Second-trimester maternal serum placental growth factor and vascular endothelial growth factor for predicting severe, early-onset preeclampsia. Obstet Gynecol 2003; 101:1266.
  110. Thadhani R, Mutter WP, Wolf M, et al. First trimester placental growth factor and soluble fms-like tyrosine kinase 1 and risk for preeclampsia. J Clin Endocrinol Metab 2004; 89:770.
  111. Rana S, Powe CE, Salahuddin S, et al. Angiogenic factors and the risk of adverse outcomes in women with suspected preeclampsia. Circulation 2012; 125:911.
  112. Moore AG, Young H, Keller JM, et al. Angiogenic biomarkers for prediction of maternal and neonatal complications in suspected preeclampsia. J Matern Fetal Neonatal Med 2012; 25:2651.
  113. Chaiworapongsa T, Romero R, Korzeniewski SJ, et al. Plasma concentrations of angiogenic/anti-angiogenic factors have prognostic value in women presenting with suspected preeclampsia to the obstetrical triage area: a prospective study. J Matern Fetal Neonatal Med 2014; 27:132.
  114. Widmer M, Villar J, Benigni A, et al. Mapping the theories of preeclampsia and the role of angiogenic factors: a systematic review. Obstet Gynecol 2007; 109:168.
  115. Gilbert JS, Ryan MJ, LaMarca BB, et al. Pathophysiology of hypertension during preeclampsia: linking placental ischemia with endothelial dysfunction. Am J Physiol Heart Circ Physiol 2008; 294:H541.
  116. Nagamatsu T, Fujii T, Kusumi M, et al. Cytotrophoblasts up-regulate soluble fms-like tyrosine kinase-1 expression under reduced oxygen: an implication for the placental vascular development and the pathophysiology of preeclampsia. Endocrinology 2004; 145:4838.
  117. Rajakumar A, Doty K, Daftary A, et al. Impaired oxygen-dependent reduction of HIF-1alpha and -2alpha proteins in pre-eclamptic placentae. Placenta 2003; 24:199.
  118. Bdolah Y, Lam C, Rajakumar A, et al. Twin pregnancy and the risk of preeclampsia: bigger placenta or relative ischemia? Am J Obstet Gynecol 2008; 198:428.e1.
  119. Burke SD, Zsengellér ZK, Khankin EV, et al. Soluble fms-like tyrosine kinase 1 promotes angiotensin II sensitivity in preeclampsia. J Clin Invest 2016; 126:2561.
  120. Buhl KB, Friis UG, Svenningsen P, et al. Urinary plasmin activates collecting duct ENaC current in preeclampsia. Hypertension 2012; 60:1346.
  121. Thadhani R, Kisner T, Hagmann H, et al. Pilot study of extracorporeal removal of soluble fms-like tyrosine kinase 1 in preeclampsia. Circulation 2011; 124:940.
  122. Kumasawa K, Ikawa M, Kidoya H, et al. Pravastatin induces placental growth factor (PGF) and ameliorates preeclampsia in a mouse model. Proc Natl Acad Sci U S A 2011; 108:1451.
  123. Rana S, Rajakumar A, Geahchan C, et al. Ouabain inhibits placental sFlt1 production by repressing HSP27-dependent HIF-1α pathway. FASEB J 2014; 28:4324.
  124. Thadhani R, Hagmann H, Schaarschmidt W, et al. Removal of Soluble Fms-Like Tyrosine Kinase-1 by Dextran Sulfate Apheresis in Preeclampsia. J Am Soc Nephrol 2016; 27:903.
  125. Venkatesha S, Toporsian M, Lam C, et al. Soluble endoglin contributes to the pathogenesis of preeclampsia. Nat Med 2006; 12:642.
  126. Luft FC. Soluble endoglin (sEng) joins the soluble fms-like tyrosine kinase (sFlt) receptor as a pre-eclampsia molecule. Nephrol Dial Transplant 2006; 21:3052.
  127. Levine RJ, Lam C, Qian C, et al. Soluble endoglin and other circulating antiangiogenic factors in preeclampsia. N Engl J Med 2006; 355:992.
  128. Staff AC, Braekke K, Johnsen GM, et al. Circulating concentrations of soluble endoglin (CD105) in fetal and maternal serum and in amniotic fluid in preeclampsia. Am J Obstet Gynecol 2007; 197:176.e1.
  129. Redman CW, Sargent IL. Latest advances in understanding preeclampsia. Science 2005; 308:1592.
  130. Germain SJ, Sacks GP, Sooranna SR, et al. Systemic inflammatory priming in normal pregnancy and preeclampsia: the role of circulating syncytiotrophoblast microparticles. J Immunol 2007; 178:5949.
  131. Hartley JD, Ferguson BJ, Moffett A. The role of shed placental DNA in the systemic inflammatory syndrome of preeclampsia. Am J Obstet Gynecol 2015; 213:268.
  132. Levine RJ, Qian C, Leshane ES, et al. Two-stage elevation of cell-free fetal DNA in maternal sera before onset of preeclampsia. Am J Obstet Gynecol 2004; 190:707.
  133. Rajakumar A, Cerdeira AS, Rana S, et al. Transcriptionally active syncytial aggregates in the maternal circulation may contribute to circulating soluble fms-like tyrosine kinase 1 in preeclampsia. Hypertension 2012; 59:256.
  134. Tannetta DS, Dragovic RA, Gardiner C, et al. Characterisation of syncytiotrophoblast vesicles in normal pregnancy and pre-eclampsia: expression of Flt-1 and endoglin. PLoS One 2013; 8:e56754.