Placental-specific sFLT-1: Role in pre-eclamptic pathophysiology and its translational possibilities for clinical prediction and diagnosis

Molecular Human Reproduction

Volumn 23, Issue 2, 2017, Pages 69-78

  Palmer, K R ^a,b   Tong, S ^b   Kaitu'u Lino, T J ^b  

^a MONASH UNIVERSITY   (Australia)

^b UNIVERSITY OF MELBOURNE   (Australia)

Author keywords

Anti angiogenic factors; Hypoxia; Placenta; Pre eclampsia; sFLT 1; Splice variant; VEGF

Indexed keywords

MESSENGER RNA; VASCULOTROPIN; VASCULOTROPIN RECEPTOR 1; BIOLOGICAL MARKER; FLT1 PROTEIN, HUMAN; ISOPROTEIN; PGF PROTEIN, HUMAN; PLACENTAL GROWTH FACTOR; VASCULOTROPIN A; VEGFA PROTEIN, HUMAN;

CLINICAL PRACTICE; GENE EXPRESSION; GENE EXPRESSION REGULATION; GENE OVEREXPRESSION; GENETIC VARIABILITY; HUMAN; NONHUMAN; PATHOPHYSIOLOGY; PLACENTA; PREDICTION; PREECLAMPSIA; PRIORITY JOURNAL; PROTEIN ANALYSIS; PROTEIN EXPRESSION; PROTEIN FUNCTION; REVIEW; ALTERNATIVE RNA SPLICING; ANIMAL; ENZYMOLOGY; FEMALE; GENETICS; METABOLISM; MOUSE; PATHOLOGY; PREGNANCY; TRANSGENIC MOUSE; VASCULAR ENDOTHELIUM; VASCULARIZATION;

ALTERNATIVE SPLICING; ANIMALS; BIOMARKERS; ENDOTHELIUM, VASCULAR; FEMALE; HUMANS; MICE; MICE, TRANSGENIC; PLACENTA; PLACENTA GROWTH FACTOR; PRE-ECLAMPSIA; PREGNANCY; PROTEIN ISOFORMS; VASCULAR ENDOTHELIAL GROWTH FACTOR A; VASCULAR ENDOTHELIAL GROWTH FACTOR RECEPTOR-1;

EID: 85021197517     PISSN: 13609947     EISSN: 14602407     Source Type: Journal    
DOI: 10.1093/molehr/gaw077     Document Type: Review

References (91)

1. Ahmad S, Ahmed A. Elevated placental soluble vascular endothelial growth factor receptor-1 inhibits angiogenesis in preeclampsia. Circ Res 2004; 95:884-891.
2. Andersen LB, Dechend R, Jorgensen JS, Luef BM, Nielsen J, Barington T, Christesen HT. Prediction of preeclampsia with angiogenic biomarkers. Results from the prospective odense child cohort. Hypertens Pregnancy 2016;35:405-419.
3. Bdolah Y, Lam C, Rajakumar A, Shivalingappa V, Mutter W, Sachs BP, Lim KH, Bdolah-Abram T, Epstein FH, Karumanchi SA. Twin pregnancy and the risk of preeclampsia: bigger placenta or relative ischemia? Am J Obstet Gynecol 2008;198:428, e421-426.
4. Benton SJ, Hu Y, Xie F, Kupfer K, Lee SW, Magee LA, von Dadelszen P. Angiogenic factors as diagnostic tests for preeclampsia: a performance comparison between two commercial immunoassays. Am J Obstet Gynecol 2011;205:469, e461-468.
5. Bergmann A, Ahmad S, Cudmore M, Gruber AD, Wittschen P, Lindenmaier W, Christofori G, Gross V, Gonzalves A, Grone HJ et al. Reduction of circulating soluble Flt-1 alleviates preeclampsia-like symptoms in a mouse model. J Cell Mol Med 2010;14:1857-1867.
6. Boeckel JN, Guarani V, Koyanagi M, Roexe T, Lengeling A, Schermuly RT, Gellert P, Braun T, Zeiher A, Dimmeler S. Jumonji domain-containing protein 6 (Jmjd6) is required for angiogenic sprouting and regulates splicing of VEGF-receptor 1. Proc Natl Acad Sci USA 2011;108:3276-3281.
7. Brownfoot FC, Hastie R, Hannan NJ, Cannon P, Tuohey L, Parry LJ, Senadheera S, Illanes SE, Kaitu'u-Lino TJ, Tong S. Metformin as a prevention and treatment for preeclampsia: effects on soluble fms-like tyrosine kinase 1 and soluble endoglin secretion and endothelial dysfunction. Am J Obstet Gynecol 2016;214:356, e351-356, e315.
8. Brownfoot FC, Tong S, Hannan NJ, Binder NK, Walker SP, Cannon P, Hastie R, Onda K, Kaitu'u-Lino TJ. Effects of pravastatin on human placenta, endothelium, and women with severe preeclampsia. Hypertension 2015a;66:687-697. discussion 445.
9. Brownfoot FC, Tong S, Hannan NJ, Hastie R, Cannon P, Tuohey L, Kaitu'u-Lino TJ. YC-1 reduces placental sFlt-1 and soluble endoglin production and decreases endothelial dysfunction: a possible therapeutic for preeclampsia. Mol Cell Endocrinol 2015b;413:202-208.
10. Chaiworapongsa T, Romero R, Espinoza J, Bujold E, Mee Kim Y, Goncalves LF, Gomez R, Edwin S. 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;190:1541-1547. discussion 1547-1550.
11. Chesley LC. History and epidemiology of preeclampsia-eclampsia. Clin Obstet Gynecol 1984;27:801-820.
12. Christinger HW, Fuh G, de Vos AM, Wiesmann C. The crystal structure of placental growth factor in complex with domain 2 of vascular endothelial growth factor receptor-1. J Biol Chem 2004;279:10382-10388.
13. Clark DE, Smith SK, He Y, Day KA, Licence DR, Corps AN, Lammoglia R, Charnock-Jones DS. A vascular endothelial growth factor antagonist is produced by the human placenta and released into the maternal circulation. Biol Reprod 1998;59:1540-1548.
14. Eremina V, Jefferson JA, Kowalewska J, Hochster H, Haas M, Weisstuch J, Richardson C, Kopp JB, Kabir MG, Backx PH et al. VEGF inhibition and renal thrombotic microangiopathy. N Engl J Med 2008; 358:1129-1136.
15. Eremina V SM, Haigh J, Nagy A, Lajoie G, Ferrara N, Gerber HP, Kikkawa Y, Miner JH, Quaggin SE. Glomerular-specific alterations of VEGF-A expression lead to distinct congenital and acquired renal diseases. J Clin Invest 2003;111:707-716.
16. Gerber HP, Condorelli F, Park J, Ferrara N. Differential transcriptional regulation of the two vascular endothelial growth factor receptor genes. Flt-1, but not Flk-1/KDR, is up-regulated by hypoxia. J Biol Chem 1997; 272:23659-23667.
17. Gilbert JS, Babcock SA, Granger JP. Hypertension produced by reduced uterine perfusion in pregnant rats is associated with increased soluble fms-like tyrosine kinase-1 expression. Hypertension 2007;50:1142-1147.
18. Glusker P, Recht L, Lane B. Reversible posterior leukoencephalopathy syndrome and bevacizumab. N Engl J Med 2006;354:980-982.
19. Gu Y, Lewis DF, Wang Y. Placental productions and expressions of soluble endoglin, soluble fms-like tyrosine kinase receptor-1, and placental growth factor in normal and preeclamptic pregnancies. J Clin Endocrinol Metab 2008;93:260-266.
20. Han KY, Dugas-Ford J, Lee H, Chang JH, Azar DT. MMP14 cleavage of VEGFR1 in the cornea leads to a VEGF-trap antiangiogenic effect. Invest Ophthalmol Vis Sci 2015;56:5450-5456.
21. He H, Venema VJ, Gu X, Venema RC, Marrero MB, Caldwell RB. Vascular endothelial growth factor signals endothelial cell production of nitric oxide and prostacyclin through flk-1/KDR activation of c-Src. J Biol Chem 1999a;274:25130-25135.
22. He Y, Smith SK, Day KA, Clark DE, Licence DR, Charnock-Jones DS. Alternative splicing of vascular endothelial growth factor (VEGF)-R1 (FLT-1) pre-mRNA is important for the regulation of VEGF activity. Mol Endocrinol 1999b;13:537-545.
23. Hertig A, Berkane N, Lefevre G, Toumi K, Marti HP, Capeau J, Uzan S, Rondeau E. Maternal serum sFlt1 concentration is an early and reliable predictive marker of preeclampsia. Clin Chem 2004;50:1702-1703.
24. Heydarian M, McCaffrey T, Florea L, Yang Z, Ross MM, Zhou W, Maynard SE. Novel splice variants of sFlt1 are upregulated in preeclampsia. Placenta 2009;30:250-255.
25. Iriyama T, Sun K, Parchim NF, Li J, Zhao C, Song A, Hart LA, Blackwell SC, Sibai BM, Chan LN et al. Elevated placental adenosine signaling contributes to the pathogenesis of preeclampsia. Circulation 2015;131: 730-741.
26. Jebbink J, Keijser R, Veenboer G, van der Post J, Ris-Stalpers C, Afink G. Expression of placental FLT1 transcript variants relates to both gestational hypertensive disease and fetal growth. Hypertension 2011;58:70-76.
27. Johnson S, Bonello M, Li Z, Hilder L, Sullivan E. Maternal deaths in Australia 2006-2010. Canberra: Australian Institute of Health and Welfare, 2014, Maternal death series no.4; Cat no. PER 61.
28. Kandula P, Agarwal R. Proteinuria and hypertension with tyrosine kinase inhibitors. Kidney Int 2011;80:1271-1277.
29. Kanter D, Lindheimer MD, Wang E, Borromeo RG, Bousfield E, Karumanchi SA, Stillman IE. Angiogenic dysfunction in molar pregnancy. Am J Obstet Gynecol 2010;202:e181-e185.
30. Kendall RL, Thomas KA. Inhibition of vascular endothelial cell growth factor activity by an endogenously encoded soluble receptor. Proc Natl Acad Sci USA 1993;90:10705-10709.
31. Kendall RL, Wang G, DiSalvo J, Thomas KA. Specificity of vascular endothelial cell growth factor receptor ligand binding domains. Biochem Biophys Res Commun 1994;201:326-330.
32. Koga K, Osuga Y, Tajima T, Hirota Y, Igarashi T, Fujii T, Yano T, Taketani Y. Elevated serum soluble fms-like tyrosine kinase 1 (sFlt1) level in women with hydatidiform mole. Fertil Steril 2010;94:305-308.
33. Kumasawa K, Ikawa M, Kidoya H, Hasuwa H, Saito-Fujita T, Morioka Y, Takakura N, Kimura T, Okabe M. Pravastatin induces placental growth factor (PGF) and ameliorates preeclampsia in a mouse model. Proc Natl Acad Sci U S A 2011;108:1451-1455.
34. Leung DW, Cachianes G, Kuang WJ, Goeddel DV, Ferrara N. Vascular endothelial growth factor is a secreted angiogenic mitogen. Science 1989;246:1306-1309.
35. Levine RJ, Maynard SE, Qian C, Lim K-H, England LJ, Yu KF, Schisterman EF, Thadhani R, Sachs BP, Epstein FH et al. Circulating angiogenic factors and the risk of preeclampsia. N Engl J Med 2004;350:672-683.
36. Levine RJ, Qian C, Maynard SE, Yu KF, Epstein FH, Karumanchi SA. Serum sFlt1 concentration during preeclampsia and mid trimester blood pressure in healthy nulliparous women. Am J Obstet Gynecol 2006;194:1034-1041.
37. Li C, Raikwar NS, Santillan MK, Santillan DA, Thomas CP. Aspirin inhibits expression of sFLT1 from human cytotrophoblasts induced by hypoxia, via cyclo-oxygenase 1. Placenta 2015;36:446-453.
38. Liu Y, Zhao Y, Yu A, Zhao B, Gao Y, Niu H. Diagnostic accuracy of the soluble Fms-like tyrosine kinase-1/placental growth factor ratio for preeclampsia: a meta-analysis based on 20 studies. Arch Gynecol Obstet 2015;292:507-518.
39. Livingston JC, Chin R, Haddad B, McKinney ET, Ahokas R, Sibai BM. Reductions of vascular endothelial growth factor and placental growth factor concentrations in severe preeclampsia. Am J Obstet Gynecol 2000; 183:1554-1557.
40. Maharaj AS, D'Amore PA. Roles for VEGF in the adult. Microvasc Res 2007;74:100-113.
41. Makris A, Thornton C, Thompson J, Thomson S, Martin R, Ogle R, Waugh R, McKenzie P, Kirwan P, Hennessy A. Uteroplacental ischemia results in proteinuric hypertension and elevated sFLT-1. Kidney Int 2007; 71:977-984.
42. Matlin AJ, Clark F, Smith CW. Understanding alternative splicing: towards a cellular code. Nat Rev Mol Cell Biol 2005;6:386-398.
43. Maynard S, Min J, Merchan J, Lim K, Li J, Mondal S, Libermann T, Morgan J, Sellke F, Stillman I et al. Excess placental soluble fms-like tyrosine kinase 1 (sFlt-1) may contribute to endothelial dysfunction, hypertension, and proteinuria in pre-eclampsia. J Clin Invest 2003;111:649-658.
44. Maynard SE, Crawford SL, Bathgate S, Yan J, Robidoux L, Moore M, Moore Simas TA. Gestational angiogenic biomarker patterns in high risk preeclampsia groups. Am J Obstet Gynecol 2013;209:53 e51-59.
45. McKeeman GC, Ardill JE, Caldwell CM, Hunter AJ, McClure N. Soluble vascular endothelial growth factor receptor-1 (sFlt-1) is increased throughout gestation in patients who have preeclampsia develop. Am J Obstet Gynecol 2004;191:1240-1246.
46. Mighell AJ, Markham AF, Robinson PA. Alu sequences. FEBS Lett 1997; 417:1-5.
47. Mol BW, Roberts CT, Thangaratinam S, Magee LA, de Groot CJ, Hofmeyr GJ. Pre-eclampsia. Lancet 2016;387:999-1011.
48. Myatt L, Roberts JM. Preeclampsia: syndrome or disease? Curr Hypertens Rep 2015;17:83.
49. Nagamatsu T, Fujii T, Kusumi M, Zou L, Yamashita T, Osuga Y, Momoeda M, Kozuma S, Taketani Y. 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;145:4838-4845.
50. Ness RB, Roberts JM. Heterogeneous causes constituting the single syndrome of preeclampsia: a hypothesis and its implications. Am J Obstet Gynecol 1996;175:1365-1370.
51. Ozcan C, Wong SJ, Hari P. Reversible posterior leukoencephalopathy syndrome and bevacizumab. N Engl J Med 2006;354:980-982.
52. Palmer KR, Kaitu'u-Lino TJ, Cannon P, Tuohey L, De Silva MS, Varas-Godoy M, Acuna S, Galaz J, Tong S, Illanes SE. Maternal plasma concentrations of the placental specific sFLT-1 variant, sFLT-1 e15a, in fetal growth restriction and preeclampsia. J Matern Fetal Neonatal Med 2016a;16:1-5.
53. Palmer KR, Kaitu'u-Lino TJ, Hastie R, Hannan NJ, Ye L, Binder N, Cannon P, Tuohey L, Johns TG, Shub A et al. Placental-specific sFLT-1 e15a protein is increased in preeclampsia, antagonizes vascular endothelial growth factor signaling, and has antiangiogenic activity. Hypertension 2015;66: 1251-1259.
54. Palmer KR, Tong S, Tuohey L, Cannon P, Ye L, Hannan NJ, Brownfoot FC, Illanes SE, Kaitu'u-Lino TJ. Jumonji domain containing protein 6 is decreased in human preeclamptic placentas and regulates sFLT-1 splice variant production. Biol Reprod 2016b;94:59.
55. Park JE, Chen HH, Winer J, Houck KA, Ferrara N. Placenta growth factor. Potentiation of vascular endothelial growth factor bioactivity, in vitro and in vivo, and high affinity binding to Flt-1 but not to Flk-1/KDR. J Biol Chem 1994;269:25646-25654.
56. Park M, Lee ST. The fourth immunoglobulin-like loop in the extracellular domain of FLT-1, a VEGF receptor, includes a major heparin-binding site. Biochem Biophys Res Commun 1999;264:730-734.
57. Powers RW, Roberts JM, Cooper KM, Gallaher MJ, Frank MP, Harger GF, Ness RB. Maternal serum soluble fms-like tyrosine kinase 1 concentrations are not increased in early pregnancy and decrease more slowly postpartum in women who develop preeclampsia. Am J Obstet Gynecol 2005;193:185-191.
58. Rahimi N, Golde TE, Meyer RD. Identification of ligand-induced proteolytic cleavage and ectodomain shedding of VEGFR-1/FLT1 in leukemic cancer cells. Cancer Res 2009;69:2607-2614.
59. Raikwar NS, Liu KZ, Thomas CP. N-terminal cleavage and release of the ectodomain of Flt1 is mediated via ADAM10 and ADAM 17 and regulated by VEGFR2 and the Flt1 intracellular domain. PLoS One 2014;9: e112794.
60. Raikwar NS, Liu KZ, Thomas CP. Ectodomain cleavage of FLT1 regulates receptor activation and function and is not required for its downstream intracellular cleavage. Exp Cell Res 2016;344:103-111.
61. Rajakumar A, Michael HM, Rajakumar PA, Shibata E, Hubel CA, Karumanchi SA, Thadhani R, Wolf M, Harger G, Markovic N. Extraplacental expression of vascular endothelial growth factor receptor-1, (Flt-1) and soluble Flt-1 (sFlt-1), by peripheral blood mononuclear cells (PBMCs) in normotensive and preeclamptic pregnant women. Placenta 2005;26:563-573.
62. Rana S, Rajakumar A, Geahchan C, Salahuddin S, Cerdeira AS, Burke SD, George EM, Granger JP, Karumanchi SA. Ouabain inhibits placental sFlt1 production by repressing HSP27-dependent HIF-1alpha pathway. FASEB J 2014;28:4324-4334.
63. Raymond D, Peterson E. A critical review of early-onset and late-onset preeclampsia. Obstet Gynecol Surv 2011;66:497-506.
64. Say L, Chou D, Gemmill A, Tuncalp O, Moller AB, Daniels J, Gulmezoglu AM, Temmerman M, Alkema L. Global causes of maternal death: a WHO systematic analysis. Lancet Glob Health 2014;2:e323-333.
65. Schiettecatte J, Russcher H, Anckaert E, Mees M, Leeser B, Tirelli AS, Fiedler GM, Luthe H, Denk B, Smitz J. Multicenter evaluation of the first automated Elecsys sFlt-1 and PlGF assays in normal pregnancies and preeclampsia. Clin Biochem 2010;43:768-770.
66. Sela S, Itin A, Natanson-Yaron S, Greenfield C, Goldman-Wohl D, Yagel S, Keshet E. A novel human-specific soluble vascular endothelial growth factor receptor 1: cell type-specific splicing and implications to vascular endothelial growth factor homeostasis and preeclampsia. Circ Res 2008; 102:1566-1574.
67. Shibata E, Rajakumar A, Powers RW, Larkin RW, Gilmour C, Bodnar LM, Crombleholme WR, Ness RB, Roberts JM, Hubel CA. Soluble fms-like tyrosine kinase 1 is increased in preeclampsia but not in normotensive pregnancies with small-for-gestational-age neonates: relationship to circulating placental growth factor. J Clin Endocrinol Metab 2005;90:4895-4903.
68. Shibuya M, Yamaguchi S, Yamane A, Ikeda T, Tojo A, Matsushime H, Sato M. Nucleotide sequence and expression of a novel human receptor-type tyrosine kinase gene (flt) closely related to the fms family. Oncogene 1990; 5:519-524.
69. Souders CA, Maynard SE, Yan J,Wang Y, Boatright NK, Sedan J, Balyozian D, Cheslock PS, Molrine DC, Simas TA. Circulating levels of sFlt1 splice variants as predictive markers for the development of preeclampsia. Int J Mol Sci 2015;16:12436-12453.
70. Steegers EA, von Dadelszen P, Duvekot JJ, Pijnenborg R. Pre-eclampsia. Lancet 2010;376:631-644.
71. Sugimoto H, Hamano Y, Charytan D, Cosgrove D, Kieran M, Sudhakar A, Kalluri R. Neutralization of circulating vascular endothelial growth factor (VEGF) by anti-VEGF antibodies and soluble VEGF receptor 1 (sFlt-1) induces proteinuria. J Biol Chem 2003;278:12605-12608.
72. Suwaki N, Masuyama H, Nakatsukasa H, Masumoto A, Sumida Y, Takamoto N, Hiramatrsu Y. Hypoadiponectinemia and circulating angiogenic factors in overweight patients complicated with pre-eclampsia. Am J Obstet Gynecol 2006;195:1687-1692.
73. Szalai G, Romero R, Chaiworapongsa T, Xu Y, Wang B, Ahn H, Xu Z, Chiang PJ, Sundell B, Wang R et al. Full-length human placental sFlt-1- e15a isoform induces distinct maternal phenotypes of preeclampsia in mice. PLoS One 2015;10:e0119547.
74. Szalai G, Xu Y, Romero R, Chaiworapongsa T, Xu Z, Chiang PJ, Ahn H, Sundell B, Plazyo O, Jiang Y et al. In vivo experiments reveal the good, the bad and the ugly faces of sFlt-1 in pregnancy. PLoS One 2014;9: e110867.
75. Tal R, Shaish A, Barshack I, Polak-Charcon S, Afek A, Volkov A, Feldman B, Avivi C, Harats D. Effects of hypoxia-inducible factor-1[alpha] overexpression in pregnant mice: possible implications for preeclampsia and intrauterine growth restriction. Am J Pathol 2010;177:2950-2962.
76. Thadhani R, Hagmann H, Schaarschmidt W, Roth B, Cingoez T, Karumanchi SA, Wenger J, Lucchesi KJ, Tamez H, Lindner T et al. Removal of soluble Fms-like tyrosine kinase-1 by dextran sulfate apheresis in preeclampsia. J Am Soc Nephrol 2016;27:903-913.
77. Thomas CP, Andrews JI, Liu KZ. Intronic polyadenylation signal sequences and alternate splicing generate human soluble Flt1 variants and regulate the abundance of soluble Flt1 in the placenta. FASEB J 2007;21: 3885-3895.
78. Thomas CP, Andrews JI, Raikwar NS, Kelley EA, Herse F, Dechend R, Golos TG, Liu KZ. A recently evolved novel trophoblast-enriched secreted form of fms-like tyrosine kinase-1 variant is up-regulated in hypoxia and preeclampsia. J Clin Endocrinol Metab 2009;94:2524-2530.
79. Thornton JG, Onwude JL. Convulsions in pregnancy in related gorillas. Am J Obstet Gynecol 1992;167:240-241.
80. Tranquilli AL, Dekker G, Magee L, Roberts J, Sibai BM, Steyn W, Zeeman GG, Brown MA. The classification, diagnosis and management of the hypertensive disorders of pregnancy: a revised statement from the ISSHP. Pregnancy Hypertens 2014;4:97-104.
81. Vatish M, Strunz-McKendry T, Hund M, Allegranza D, Wolf C, Smare C. The sflt-1/plgf ratio test in pre-eclampsia: an economic assessment for the UK. Ultrasound Obstet Gynecol 2016.
82. Venkatesha S, Toporsian M, Lam C, Hanai J, Mammoto T, Kim YM, Bdolah Y, Lim KH, Yuan HT, Libermann TA et al. Soluble endoglin contributes to the pathogenesis of preeclampsia. Nat Med 2006;12: 642-649.
83. Verlohren S, Stepan H, Dechend R. Angiogenic growth factors in the diagnosis and prediction of pre-eclampsia. Clin Sci 2012;122:43-52.
84. Vidal F, Aragones J, Alfranca A, de Landazuri MO. Up-regulation of vascular endothelial growth factor receptor Flt-1 after endothelial denudation: role of transcription factor Egr-1. Blood 2000;95:3387-3395.
85. Villa PM, Hamalainen E, Maki A, Raikkonen K, Pesonen AK, Taipale P, Kajantie E, Laivuori H. Vasoactive agents for the prediction of early- and late-onset preeclampsia in a high-risk cohort. BMC Pregnancy Childbirth 2013;13:110.
86. Whitehead CL, Palmer KR, Nilsson U, Gao Y, Saglam B, Lappas M, Tong S. Placental expression of a novel primate-specific splice variant of sFlt-1 is upregulated in pregnancies complicated by severe early onset pre-eclampsia. BJOG 2011;118:1268-1271.
87. WHO World Health Report: Making Every Mother and Child Count. Geneva: World Health Organisation, 2005.
88. Wiesmann C, Fuh G, Christinger HW, Eigenbrot C, Wells JA, de Vos AM. Crystal structure at 1.7 A resolution of VEGF in complex with domain 2 of the Flt-1 receptor. Cell 1997;91:695-704.
89. Wikstrom A-K, Larsson A, Eriksson UJ, Nash P, Nordén-Lindeberg S, Olovsson M. Placental growth factor and soluble FMS-like tyrosine kinase-1 in early-onset and late-onset preeclampsia. Obstet Gynecol 2007;109:1368-1374. 1310.1097/1301.AOG.0000264552.000028543 6.a0000264551.
90. Xiong Y, Liebermann DA, Tront JS, Holtzman EJ, Huang Y, Hoffman B, Geifman-Holtzman O. Gadd45a stress signaling regulates sFlt-1 expression in preeclampsia. J Cell Physiol 2009;220: 632-639.
91. Zeisler H, Llurba E, Chantraine F, Vatish M, Staff AC, Sennstrom M, Olovsson M, Brennecke SP, Stepan H, Allegranza D et al. Predictive value of the sFlt-1:PlGF ratio in women with suspected preeclampsia. N Engl J Med 2016;374:13-22.