Top

BMC Pregnancy and Childbirth

Published in:

Open Access 01-12-2016 | Research article

Effects of simvastatin, rosuvastatin and pravastatin on soluble fms-like tyrosine kinase 1 (sFlt-1) and soluble endoglin (sENG) secretion from human umbilical vein endothelial cells, primary trophoblast cells and placenta

Authors: Fiona C. Brownfoot, Stephen Tong, Natalie J. Hannan, Roxanne Hastie, Ping Cannon, Tu’uhevaha J. Kaitu’u-Lino

Published in: BMC Pregnancy and Childbirth | Issue 1/2016

Abstract

Background

Preeclampsia is associated with the placental release of soluble fms-like tyrosine kinase 1 (sFlt-1) and soluble endoglin (sENG). These anti-angiogenic factors cause hypertension and multi-organ injury. Pravastatin decreases placental secretion of sFlt-1 in vitro and is currently being examined in clinical trials as a potential treatment for preeclampsia. However, it is possible that different classes of statins may be more potent at decreasing sFlt-1 secretion. We compared the relative potency of three different generations of statins on sFlt-1 and sENG secretion from human endothelial cells, trophoblast cells, and placenta explants.

Methods

We performed functional experiments using primary human umbilical vein endothelial cells, trophoblast cells and preterm preeclamptic placental explants to assess the affect of simvastatin, rosuvastatin and pravastatin on sFlt-1 and sENG secretion and compared the relative potency of each statin at reducing these factors (Inhibitory Concentration 50). Furthermore we assessed the effect of each statin on the antioxidant and cytoprotective enzyme, heme-oxygenase 1.

Results

All statins reduced sFlt-1 secretion from endothelial cells, trophoblasts and preterm preeclamptic placental explants. Simvastatin was the most potent inhibitor of sFlt-1 secretion from endothelial cells (IC 50 3.2 μM), trophoblast cells (IC 50 61.4 μM) and placental explants. Simvastatin was 28 times and 3 times more potent at reducing sFlt-1 secretion from endothelial cells and 85 times and 33 times more potent at reducing sFlt-1 secretion from trophoblast cells than pravastatin or rosuvastatin respectively.

All statins increased sENG secretion from endothelial cells however did not change secretion from placental explants.

While all statins up-regulated heme-oxygenase 1 in endothelial cells, only simvastatin up-regulated its expression in placenta from patients with preterm preeclampsia.

Conclusion

Simvastatin may be a more potent inhibitor of sFlt-1 secretion from endothelial cells, trophoblast cells and placenta from women with preterm preeclampsia than either pravastatin or rosuvastatin.

Maynard S, Min JY, Merchan J, Lim KH, Li J, Mondal S, Libermann, TA, Morgan, JP, Sellke, FW, Stillman, IE, Epstein, FH, Sukhatme, VP, Ananth Karumanchi, S. 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(5):649–58.CrossRefPubMedPubMedCentral

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(6):642–9.CrossRefPubMed

Redman CW, Sargent IL. Latest advances in understanding preeclampsia. Science. 2005;308(5728):1592–4.CrossRefPubMed

Sibai B, Dekker G, Kupferminc M. Pre-eclampsia. Lancet. 2005;365(9461):785–99.CrossRefPubMed

Powe CE, Levine RJ, Karumanchi SA. Preeclampsia, a disease of the maternal endothelium: the role of antiangiogenic factors and implications for later cardiovascular disease. Circulation. 2011;123(24):2856–69.CrossRefPubMed

Young BC, Levine RJ, Karumanchi SA. Pathogenesis of preeclampsia. Annu Rev Pathol. 2010;5:173–92.CrossRefPubMed

Chaiworapongsa T, Chaemsaithong P, Yeo L, Romero R. Pre-eclampsia part 1: current understanding of its pathophysiology. Nat Rev Nephrol. 2014;10(8):466–80.CrossRefPubMed

Chaiworapongsa T, Chaemsaithong P, Korzeniewski SJ, Yeo L, Romero R. Pre-eclampsia part 2: prediction, prevention and management. Nat Rev Nephrol. 2014;10(9):531–40.CrossRefPubMed

Cudmore M, Ahmad S, Al-Ani B, Fujisawa T, Coxall H, Chudasama K, Devey LR, Wigmore SJ, Abbas A, Hewett PW, et al. Negative regulation of soluble Flt-1 and soluble endoglin release by heme oxygenase-1. Circulation. 2007;115(13):1789–97.CrossRefPubMed

10.

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. Hypertens. 2015;66(3):687-97.

11.

Costantine MM, Tamayo E, Lu F, Bytautiene E, Longo M, Hankins GD, Saade GR. Using pravastatin to improve the vascular reactivity in a mouse model of soluble fms-like tyrosine kinase-1-induced preeclampsia. Obstet Gynecol. 2010;116(1):114–20.CrossRefPubMed

12.

Fox KA, Longo M, Tamayo E, Kechichian T, Bytautiene E, Hankins GD, Saade GR, Costantine MM. Effects of pravastatin on mediators of vascular function in a mouse model of soluble Fms-like tyrosine kinase-1-induced preeclampsia. Am J Obstet Gynecol. 2011;205(4):366. e361-365.CrossRefPubMed

13.

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(4):1451–5.CrossRefPubMed

14.

Bauer AJ, Banek CT, Needham K, Gillham H, Capoccia S, Regal JF, Gilbert JS. Pravastatin attenuates hypertension, oxidative stress, and angiogenic imbalance in rat model of placental ischemia-induced hypertension. Hypertension. 2013;61(5):1103–10.CrossRefPubMedPubMedCentral

15.

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(4):1034–41.CrossRefPubMed

16.

Thadhani R, Kisner T, Hagmann H, Bossung V, Noack S, Schaarschmidt W, Jank A, Kribs A, Cornely OA, Kreyssig C, et al. Pilot study of extracorporeal removal of soluble fms-like tyrosine kinase 1 in preeclampsia. Circulation. 2011;124(8):940–50.CrossRefPubMed

17.

Kapur NK, Musunuru K. Clinical efficacy and safety of statins in managing cardiovascular risk. Vasc Health Risk Manag. 2008;4(2):341–53.CrossRefPubMedPubMedCentral

18.

The StAmP Trial: A Proof of Principle, Double-Blind, Randomised Placebo-Controlled, Multi Centre Trial of pravaStatin to Ameliorate Early Onset Pre-eclampsia. 2012.

19.

Costantine MM, Cleary K. Pravastatin for the prevention of preeclampsia in high-risk pregnant women. Obstet Gynecol. 2013;121(2 Pt 1):349–53.CrossRefPubMed

20.

Brownfoot FC, Hannan N, Onda K, Tong S, Kaitu’u-Lino T. Soluble endoglin production is upregulated by oxysterols but not quenched by pravastatin in primary placental and endothelial cells. Placenta. 2014;35(9):724–31.CrossRefPubMed

21.

Kaitu’u-Lino TJ, Tong S, Beard S, Hastie R, Tuohey L, Brownfoot F, Onda K, Hannan NJ. Characterization of protocols for primary trophoblast purification, optimized for functional investigation of sFlt-1 and soluble endoglin. Pregnancy Hypertens. 2014;4(4):287–95.PubMed

22.

ACOG. Report of the american college of obstetricians and gynecologists’ task force on hypertension in pregnancy. Obstet and gynecol. 2013;122:1122–31.CrossRef

23.

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(10):1268–71.CrossRefPubMed

24.

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(1):70–6.CrossRefPubMed

25.

Lecarpentier EMO, Fournier T, Elefant E, Chavatte-Palmer P, Tsatsaris V. Statins and pregnancy. Drugs. 2012;72(6):773–88.CrossRefPubMed

26.

Nanovskaya TN, Patrikeeva SL, Paul J, Costantine MM, Hankins GD, Ahmed MS. Transplacental transfer and distribution of pravastatin. Am J Obstet Gynecol. 2013;209(4):373. e371-375.CrossRefPubMedPubMedCentral

27.

Nachtigal P, Pospisilova N, Vecerova L, Micuda S, Brcakova E, Pospechova K, Semecky V. Atorvastatin increases endoglin, SMAD2, phosphorylated SMAD2/3 and eNOS expression in ApoE/LDLR double knockout mice. J Atheroscler Thromb. 2009;16(3):265–74.CrossRefPubMed

28.

Tong S, Kaitu’u-Lino TJ, Onda K, Beard S, Hastie R, Binder NK, Cluver C, Tuohey L, Whitehead C, Brownfoot F, et al. Heme oxygenase-1 is not decreased in preeclamptic placenta and does not negatively regulate placental soluble fms-like tyrosine kinase-1 or soluble endoglin secretion. Hypertension. 2015;66(5):1073–81.CrossRefPubMed

29.

Edison RJ, Muenke M. Mechanistic and epidemiologic considerations in the evaluation of adverse birth outcomes following gestational exposure to statins. Am J Med Genet A. 2004;131(3):287–98.CrossRefPubMed

30.

Petersen EE, Mitchell AA, Carey JC, Werler MM, Louik C, Rasmussen SA, National Birth Defects Prevention S. Maternal exposure to statins and risk for birth defects: a case-series approach. Am J Med Genet A. 2008;146A(20):2701–5.CrossRefPubMed

31.

Bateman BT, Hernandez-Diaz S, Fischer MA, Seely EW, Ecker JL, Franklin JM, Desai RJ, Allen-Coleman C, Mogun H, Avorn J, et al. Statins and congenital malformations: cohort study. BMJ. 2015;350:h1035.CrossRefPubMedPubMedCentral

32.

Gibb H, Scialli AR. Statin drugs and congenital anomalies. Am J Med Genet A. 2005;135(2):230–1. author reply 232–234.CrossRefPubMed

Title: Effects of simvastatin, rosuvastatin and pravastatin on soluble fms-like tyrosine kinase 1 (sFlt-1) and soluble endoglin (sENG) secretion from human umbilical vein endothelial cells, primary trophoblast cells and placenta
Authors: Fiona C. Brownfoot
Stephen Tong
Natalie J. Hannan
Roxanne Hastie
Ping Cannon
Tu’uhevaha J. Kaitu’u-Lino
Publication date: 01-12-2016
Publisher: BioMed Central
Published in: BMC Pregnancy and Childbirth / Issue 1/2016
Electronic ISSN: 1471-2393
DOI: https://doi.org/10.1186/s12884-016-0902-3

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Effects of simvastatin, rosuvastatin and pravastatin on soluble fms-like tyrosine kinase 1 (sFlt-1) and soluble endoglin (sENG) secretion from human umbilical vein endothelial cells, primary trophoblast cells and placenta

Abstract

Background

Methods

Results

Conclusion

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods

Results

Conclusion

Please log in to get access to this content

Other articles of this Issue 1/2016

Boosting antenatal care attendance and number of hospital deliveries among pregnant women in rural communities: a community initiative in Ghana based on mobile phones applications and portable ultrasound scans

Identification of fetal cardiac anatomy and hemodynamics: a novel enhanced screening protocol

Satisfaction with emergency obstetric and new born care services among clients using public health facilities in Jimma Zone, Oromia Regional State, Ethiopia; a cross sectional study

Cesarean section may increase the risk of both overweight and obesity in preschool children

Bacterial vaginosis and adverse outcomes among full-term infants: a cohort study

Postpartum depression in the Occupied Palestinian Territory: a longitudinal study in Bethlehem