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Soluble fms-like tyrosine kinase-1 (sFlt-1 or sVEGFR-1) is a tyrosine kinase protein with antiangiogenic properties. A non-membrane associated splice variant of VEGF receptor 1 (Flt-1), sFlt-1 binds the angiogenic factors VEGF (vascular endothelial growth factor) and PlGF (placental growth factor), reducing blood vessel growth through reduction of free VEGF and P1GF concentrations.[1] In humans, sFlt-1 is important in the regulation of blood vessel formation in diverse tissues, including the kidneys, cornea, and uterus.[2][3] Abnormally high levels of sFlt-1 have been implicated in the pathogenesis of preeclampsia.[4]

Structure

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Structural comparison of sFIt-1 and FIt-1.

sFlt-1 is a truncated form of the VEGF receptor Flt-1. Though sFlt-1 contains an extracellular domain identical to that of Flt-1, it lacks both the transmembrane and intercellular domains present in Flt-1. Instead, sFlt-1 contains a novel 31 amino acid C-terminal sequence.[5] sFlt-1 is composed of 6 immunoglobulin-like domains, with a binding site for VEGF and PIGF within the second domain from the N-terminus.[6] A sequence of 10 basic amino acids form a binding site for the anticoagulant heparin in the third domain from the N-terminus.[7] sFlt-1 has a pI of 9.51, giving the protein a positive charge at physiological pH.[8]

Biological function

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Comparison of mechanism of action of sFIt-1 and FIt-1.

Because sFlt-1 lacks the transmembrane domain that typically embeds tyrosine kinase receptors in the cell membrane, sFlt-1 travels freely in the blood circulation, and thus can travel from the tissue in which it is originally secreted to other areas of the body.[5] As it contains the same extracellular domain as Flt-1, sFlt-1 competes with Flt-1 to bind VEGF and PIGF, effectively reducing serum concentrations of these two angiogenic growth factors.[4] Though sFlt-1 can effectively dimerize, its lack of a kinase domain means that no tyrosine phosphorylation occurs upon ligand binding.[8] As a result, sFIt-1 effectively sequesters agonists of FIt-1, and has been implicated as a regulator of this receptor in the kidney, liver, and brain.[9]

Role in preeclampsia

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The placental factor theory of preeclampsia

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Preeclampsia is a pregnancy-specific condition characterized by maternal hypertension and proteinuria after the 20th week of gestation.[5] Normally, during early formation of the placenta, extravillous cytotrophoblasts, a type of specialized fetal cell, enter the spiral arteries of the uterus. This invasion spurs remodeling of the epithelial layer of these uterine arteries, increasing their conductance and decreasing their resistance to meet the increase blood flow demands of pregnancy.[10][11] Specifically, invading cytotrophoblasts achieve this change by down-regulating the expression of adhesion molecules characteristic of epithelial cells and up-regulating the expression of adhesion molecules characteristic of endothelial cells in a process known as pseudovasculogenesis.[12][13]

In preeclamptic patients, this arterial transformation is incomplete, as cytotrophoblasts fail to completely switch their adhesion molecule expression pattern to an endothelial form. The balance of pro- and anti-angiogenic factors and their receptors, including VEGF-A, PIGF, Flt1, and sFlt1, is thought to mediate this process.[5]

In women who develop preeclampsia, the sFlt-1 to PlGF ratio is higher than in normal pregnancy.[4][14] [6] sFlt-1 produced in the placenta is thought to circulate in the maternal bloodstream to act on distant tissues, explaining the multi-system endothelial dysfunction observed in women with preeclampsia.[5] In-vitro studies have linked sFlt-1 treatment to a pattern of vasoconstriction and endothelial dysfunction identical to the syndrome produced when cells are incubated with serum from preeclamptic patients.[5] Additionally, adenoviral transfer of the sFlt-1 gene to pregnant rats has been shown to produce a syndrome similar to preeclampsia.[5]

Preeclamptic regulation of sFlt-1

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Though sFlt-1 is produced in small amounts by endothelial cells and monocytes, the placenta is theorized to be the major source of sFlt-1 during pregnancy.[4] sFlt-1 mRNA shows strong expression in the placenta, and serum concentration of sFlt-1 falls significantly in patients after delivery of the placenta.[15] [16]

Expression of sFlt-1 is stimulated by hypoxic conditions. In healthy pregnancies, the placenta develops in a hypoxic environment, leading to a 20-fold increase in sFlt-1 expression.[17] In early-onset preeclamptic patients, this increase is estimated to be up to 43 times more pronounced, and may be spurred by conditions of poor uterine profusion leading to more severe local hypoxia.[18] Inhibition of nitric oxide signaling has also been associated with elevation of serum sFlt-1 in a rat model of preeclampsia; this stimulus may represent a secondary factor contributing to sFlt-1 trends in human preeclampsia as well.[19]

In addition to short-term regulation by oxygen and nitric oxide levels, genetic differences also influence Flt-1 gene splicing and resulting sFlt-1 expression levels. Women with histories of preeclampsia continue to show elevated serum levels of sFlt-1 up to 18 months postpartum, suggesting a genetic basis of sFlt-1 expression independent of pregnancy-related stimuli.[20]

Clinical significance

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PlGF and sFlt-1 concentrations measured by immunoassay in maternal blood improve the prognostic possibilities in preeclampsia, which is typically diagnosed solely on the basis of clinical symptoms, proteinuria, and uterine artery Doppler velocimetry.[21][22] Notably, increases in sFlt-1 and decreases in PIGF and VEGF can be detected at least five weeks before the onset of preeclamptic symptoms, potentially facilitating earlier diagnosis and treatment.[23] sFlt-1 changes are most predictive of early-onset preeclampsia; cases of preeclampsia incident late in pregnancy typically are accompanied only by small decreases in PIGF.[18] However, sFlt-1 elevation is also associated with other obstetric conditions such as non-preeclampsic interuterine growth retardation of the fetus, limiting its use as a discriminatory biomarker for preeclampsia.[24] Additionally, sensitivity and specificity of sFlt-1 testing is generally considered too low to enable it to serve as an effective predictor of preeclampsia.[25]

sFlt-1 involvement in the pathogenesis of preeclampsia may explain several demographic trends in incidence of the condition. The human Flt-1/sFlt-1 gene is located at 13q12; the association of fetal trisomy-13 with higher rates of preeclampsia could theoretically be explained by the additional copy of the gene.[5] Additionally, primiparous women have higher baseline levels of sFlt-1, a trend which could potentially explain the higher incidence of preeclampsia among first-time mothers.[5]

Citations

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  1. ^ Khalil, Asma; Muttukrishna, Shanthi; Harrington, Kevin; Jauniaux, Eric (2008-07-23). "Effect of Antihypertensive Therapy with Alpha Methyldopa on Levels of Angiogenic Factors in Pregnancies with Hypertensive Disorders". PLOS ONE. 3 (7): e2766. doi:10.1371/journal.pone.0002766. ISSN 1932-6203.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  2. ^ Ambati, Balamurali K.; Nozaki, Miho; Singh, Nirbhai; Takeda, Atsunobu; Jani, Pooja D.; Suthar, Tushar; Albuquerque, Romulo J. C.; Richter, Elizabeth; Sakurai, Eiji (2006-10-26). "Corneal avascularity is due to soluble VEGF receptor-1". Nature. 443 (7114): 993–997. doi:10.1038/nature05249. ISSN 1476-4687. PMC 2656128. PMID 17051153.{{cite journal}}: CS1 maint: PMC format (link)
  3. ^ Luft, Friedrich C. (2014-01-01). "Soluble fms-like tyrosine kinase-1 and atherosclerosis in chronic kidney disease". Kidney International. 85 (2): 238–240. doi:10.1038/ki.2013.402. ISSN 0085-2538.
  4. ^ a b c d Maynard, Sharon E.; Min, Jiang-Yong; Merchan, Jaime; Lim, Kee-Hak; Li, Jianyi; Mondal, Susanta; Libermann, Towia A.; Morgan, James P.; Sellke, Frank W. (2003-03-01). "Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia". Journal of Clinical Investigation. 111 (5): 649–658. doi:10.1172/JCI200317189. ISSN 0021-9738. PMID 12618519.
  5. ^ a b c d e f g h i Maynard, Sharon E.; Venkatesha, Shivalingappa; Thadhani, Ravi; Karumanchi, S. Ananth (May 2005). "Soluble Fms-like tyrosine kinase 1 and endothelial dysfunction in the pathogenesis of preeclampsia". Pediatric Research. 57 (5 Pt 2): 1R–7R. doi:10.1203/01.PDR.0000159567.85157.B7. ISSN 0031-3998. PMID 15817508.
  6. ^ a b Kendall, R. L.; Thomas, K. A. (1993-11-15). "Inhibition of vascular endothelial cell growth factor activity by an endogenously encoded soluble receptor". Proceedings of the National Academy of Sciences of the United States of America. 90 (22): 10705–10709. ISSN 0027-8424. PMID 8248162.
  7. ^ Holash, Jocelyn; Davis, Sam; Papadopoulos, Nick; Croll, Susan D.; Ho, Lillian; Russell, Michelle; Boland, Patricia; Leidich, Ray; Hylton, Donna (2002-08-20). "VEGF-Trap: a VEGF blocker with potent antitumor effects". Proceedings of the National Academy of Sciences of the United States of America. 99 (17): 11393–11398. doi:10.1073/pnas.172398299. ISSN 0027-8424. PMID 12177445.
  8. ^ a b Thadhani, Ravi; Kisner, Tuelay; Hagmann, Henning; Bossung, Verena; Noack, Stefanie; Schaarschmidt, Wiebke; Jank, Alexander; Kribs, Angela; Cornely, Oliver A. (2011-08-23). "Pilot study of extracorporeal removal of soluble fms-like tyrosine kinase 1 in preeclampsia". Circulation. 124 (8): 940–950. doi:10.1161/CIRCULATIONAHA.111.034793. ISSN 1524-4539. PMID 21810665.
  9. ^ Maynard, Sharon; Epstein, Franklin H.; Karumanchi, S. Ananth (2008). "Preeclampsia and angiogenic imbalance". Annual Review of Medicine. 59: 61–78. doi:10.1146/annurev.med.59.110106.214058. ISSN 0066-4219. PMID 17937587.
  10. ^ De Wolf, F.; Wolf-Peeters, C. De; Brosens, I.; Robertson, W.B. (1980-05-01). "The human placental bed: Electron microscopic study of trophoblastic invasion of spiral arteries". American Journal of Obstetrics and Gynecology. 137 (1): 58–70. doi:10.1016/0002-9378(80)90387-7. ISSN 0002-9378.
  11. ^ Brosens, I. A.; Robertson, W. B.; Dixon, H. G. (1972). "The role of the spiral arteries in the pathogenesis of preeclampsia". Obstetrics and Gynecology Annual. 1: 177–191. ISSN 0091-3332. PMID 4669123.
  12. ^ Zhou, Y; Damsky, C H; Chiu, K; Roberts, J M; Fisher, S J (March 1993). "Preeclampsia is associated with abnormal expression of adhesion molecules by invasive cytotrophoblasts". Journal of Clinical Investigation. 91 (3): 950–960. ISSN 0021-9738. PMID 7680671.
  13. ^ Zhou, Y.; Fisher, S. J.; Janatpour, M.; Genbacev, O.; Dejana, E.; Wheelock, M.; Damsky, C. H. (1997-05-01). "Human cytotrophoblasts adopt a vascular phenotype as they differentiate. A strategy for successful endovascular invasion?". The Journal of Clinical Investigation. 99 (9): 2139–2151. doi:10.1172/JCI119387. ISSN 0021-9738. PMC 508044. PMID 9151786.{{cite journal}}: CS1 maint: PMC format (link)
  14. ^ Levine, Richard J.; Thadhani, Ravi; Qian, Cong; Lam, Chun; Lim, Kee-Hak; Yu, Kai F.; Blink, Anastasia L.; Sachs, Benjamin P.; Epstein, Franklin H. (2005-01-05). "Urinary placental growth factor and risk of preeclampsia". JAMA. 293 (1): 77–85. doi:10.1001/jama.293.1.77. ISSN 1538-3598. PMID 15632339.
  15. ^ Hornig, C.; Barleon, B.; Ahmad, S.; Vuorela, P.; Ahmed, A.; Weich, H. A. (April 2000). "Release and complex formation of soluble VEGFR-1 from endothelial cells and biological fluids". Laboratory Investigation; a Journal of Technical Methods and Pathology. 80 (4): 443–454. ISSN 0023-6837. PMID 10780661.
  16. ^ Koga, Kaori; Osuga, Yutaka; Yoshino, Osamu; Hirota, Yasushi; Ruimeng, Xie; Hirata, Tetsuya; Takeda, Satoru; Yano, Tetsu; Tsutsumi, Osamu (May 2003). "Elevated serum soluble vascular endothelial growth factor receptor 1 (sVEGFR-1) levels in women with preeclampsia". The Journal of Clinical Endocrinology and Metabolism. 88 (5): 2348–2351. doi:10.1210/jc.2002-021942. ISSN 0021-972X. PMID 12727995.
  17. ^ Shibata, Eiji; Rajakumar, Augustine; Powers, Robert W.; Larkin, Robert W.; Gilmour, Carol; Bodnar, Lisa M.; Crombleholme, William R.; Ness, Roberta B.; Roberts, James M. (August 2005). "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". The Journal of Clinical Endocrinology and Metabolism. 90 (8): 4895–4903. doi:10.1210/jc.2004-1955. ISSN 0021-972X. PMID 15886253.
  18. ^ a b Wikström, Anna-Karin; Larsson, Anders; Eriksson, Ulf J.; Nash, Peppi; Nordén-Lindeberg, Solveig; Olovsson, Matts (June 2007). "Placental growth factor and soluble FMS-like tyrosine kinase-1 in early-onset and late-onset preeclampsia". Obstetrics and Gynecology. 109 (6): 1368–1374. doi:10.1097/01.AOG.0000264552.85436.a1. ISSN 0029-7844. PMID 17540809.
  19. ^ Bahtiyar, Mert Ozan; Buhimschi, Catalin; Ravishankar, Viswanathan; Copel, Joshua; Norwitz, Errol; Julien, Svena; Guller, Seth; Buhimschi, Irina A. (January 2007). "Contrasting effects of chronic hypoxia and nitric oxide synthase inhibition on circulating angiogenic factors in a rat model of growth restriction". American Journal of Obstetrics and Gynecology. 196 (1): 72.e1–6. doi:10.1016/j.ajog.2006.07.048. ISSN 1097-6868. PMID 17240241.
  20. ^ Wolf, Myles; Hubel, Carl A.; Lam, Chun; Sampson, Marybeth; Ecker, Jeffrey L.; Ness, Roberta B.; Rajakumar, Augustine; Daftary, Ashi; Shakir, Alia S. M. (December 2004). "Preeclampsia and future cardiovascular disease: potential role of altered angiogenesis and insulin resistance". The Journal of Clinical Endocrinology and Metabolism. 89 (12): 6239–6243. doi:10.1210/jc.2004-0548. ISSN 0021-972X. PMID 15579783.
  21. ^ HIRASHIMA, Chikako; OHKUCHI, Akihide; ARAI, Fujimi; TAKAHASHI, Kayo; SUZUKI, Hirotada; WATANABE, Takashi; KARIO, Kazuomi; MATSUBARA, Shigeki; SUZUKI, Mitsuaki (2005/09). "Establishing Reference Values for Both Total Soluble Fms-Like Tyrosine Kinase 1 and Free Placental Growth Factor in Pregnant Women". Hypertension Research. 28 (9): 727–732. doi:10.1291/hypres.28.727. ISSN 1348-4214. {{cite journal}}: Check date values in: |date= (help)
  22. ^ Thadhani, Ravi; Mutter, Walter P.; Wolf, Myles; Levine, Richard J.; Taylor, Robert N.; Sukhatme, Vikas P.; Ecker, Jeffrey; Karumanchi, S. Ananth (February 2004). "First trimester placental growth factor and soluble fms-like tyrosine kinase 1 and risk for preeclampsia". The Journal of Clinical Endocrinology and Metabolism. 89 (2): 770–775. doi:10.1210/jc.2003-031244. ISSN 0021-972X. PMID 14764795.
  23. ^ Levine, Richard J.; Maynard, Sharon E.; Qian, Cong; Lim, Kee-Hak; England, Lucinda J.; Yu, Kai F.; Schisterman, Enrique F.; Thadhani, Ravi; Sachs, Benjamin P. (2004-02-12). "Circulating angiogenic factors and the risk of preeclampsia". The New England Journal of Medicine. 350 (7): 672–683. doi:10.1056/NEJMoa031884. ISSN 1533-4406. PMID 14764923.
  24. ^ Stepan, Holger; Geide, Anne; Faber, Renaldo (2004-11-18). "Soluble fms-like tyrosine kinase 1". The New England Journal of Medicine. 351 (21): 2241–2242. doi:10.1056/NEJM200411183512123. ISSN 1533-4406. PMID 15548791.
  25. ^ Kleinrouweler, Ce; Wiegerinck, Mmj; Ris-Stalpers, C; Bossuyt, Pmm; van der Post, Jam; von Dadelszen, P; Mol, Bwj; Pajkrt, E; for the EBM CONNECT Collaboration (2012-06-01). "Accuracy of circulating placental growth factor, vascular endothelial growth factor, soluble fms-like tyrosine kinase 1 and soluble endoglin in the prediction of pre-eclampsia: a systematic review and meta-analysis". BJOG: An International Journal of Obstetrics & Gynaecology. 119 (7): 778–787. doi:10.1111/j.1471-0528.2012.03311.x. ISSN 1471-0528.
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