Alterations to the maternal circulating proteome after preeclampsia

Published:October 14, 2015DOI:


      The long-term maternal cardiovascular and metabolic implications associated with preeclampsia (PE) include risk of hypertension, heart disease, and metabolic syndrome. The objective of this study was to investigate if a recent history of PE was associated with detectable alterations in the circulating maternal proteome.

      Study Design

      Six-month postpartum plasma from women with a history of PE (n = 12) and women with uncomplicated obstetrical history (n = 12) were used for analysis. Depleted maternal plasma was analyzed by label-free liquid chromatography-mass spectrometry assay. Identified peptides were searched against the International Protein Index human database version 3.87. Exponentially modified protein abundance indices were used for comparison. Results were analyzed using pathway analysis software.


      A total of 126 eligible peptides were identified for analysis; 3 peptides were differentially expressed in the PE proteome, and an additional 5 peptides were unique to control subjects and 7 to PE subjects. PE peptide profiles were more strongly associated with markers of coagulation and complement activation compared to controls and mapped more significantly to cardiovascular disease (CVD) functions. Stratification of subjects by low (<39%) and high (≥39%) lifetime risk of CVD rather than by diagnosis produced similar findings. Comparison of controls (n = 6) to PE subjects (n = 6) without traditional cardiovascular risk factors found that while similar for body mass indices, blood pressure, and fasting lipid profiles at 6 months postpartum, PE peptide profiles continued to display stronger associations for coagulation and CVD functions. Global network analysis found that unique peptides to low-risk PE subjects were associated with cardiac infarction, CVD, and organismal injury and abnormalities.


      Markers of CVD risk and progression are evident in the maternal circulating proteome 6 months postpartum after PE. Augmentations in circulating peptide profiles occur in patients with previous PE who otherwise do not have clinically measurable cardiovascular risk factors. Our data highlight the need for the implementation of postpartum prevention programs in the PE population and identifies molecules that may be targeted for screening or therapeutic benefit.

      Key words

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to American Journal of Obstetrics & Gynecology
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Brown M.C.
        • Best K.E.
        • Pearce M.S.
        • Waugh J.
        • Robson S.C.
        • Bell R.
        Cardiovascular disease risk in women with pre-eclampsia: systematic review and meta-analysis.
        Eur J Epidemiol. 2013; 28: 1-19
        • Smith G.N.
        • Pudwell J.
        • Walker M.
        • Wen S.-W.
        Risk estimation of metabolic syndrome at one and three years after a pregnancy complicated by preeclampsia.
        J Obstet Gynaecol Can. 2012; 34: 836-841
        • Spaan J.
        • Peeters L.
        • Spaanderman M.
        • Brown M.
        Cardiovascular risk management after a hypertensive disorder of pregnancy.
        Hypertension. 2012; 60: 1368-1373
        • Manten G.T.
        • Sikkema M.J.
        • Voorbij H.A.
        • Visser G.H.
        • Bruinse H.W.
        • Franx A.
        Risk factors for cardiovascular disease in women with a history of pregnancy complicated by preeclampsia or intrauterine growth restriction.
        Hypertens Pregnancy. 2007; 26: 39-50
        • Smith G.N.
        • Walker M.C.
        • Liu A.
        • et al.
        A history of preeclampsia identifies women who have underlying cardiovascular risk factors.
        Am J Obstet Gynecol. 2009; 200: 58.e1-58.e8
        • Chambers J.C.
        • Fusi L.
        • Malik I.S.
        • Haskard D.O.
        • De Swiet M.
        • Kooner J.S.
        Association of maternal endothelial dysfunction with preeclampsia.
        JAMA. 2001; 285: 1607-1612
        • Lampinen K.H.
        • Ronnback M.
        • Kaaja R.J.
        • Groop P.H.
        Impaired vascular dilatation in women with a history of pre-eclampsia.
        J Hypertens. 2006; 24: 751-756
        • Melchiorre K.
        • Sutherland G.R.
        • Liberati M.
        • Thilaganathan B.
        Preeclampsia is associated with persistent postpartum cardiovascular impairment.
        Hypertension. 2011; 58: 709-715
        • Yuan L.J.
        • Xue D.
        • Duan Y.Y.
        • Cao T.S.
        • Yang H.G.
        • Zhou N.
        Carotid arterial intima-media thickness and arterial stiffness in pre-eclampsia: analysis with a radiofrequency ultrasound technique.
        Ultrasound Obstet Gynecol. 2013; 42: 644-652
        • Bytautiene E.
        • Bulayeva N.
        • Bhat G.
        • Li L.
        • Rosenblatt K.P.
        • Saade G.R.
        Long-term alterations in maternal plasma proteome after sFlt1-induced preeclampsia in mice.
        Am J Obstet Gynecol. 2013; 208: 388.e1-388.e10
        • Wang F.
        • Wang L.
        • Shi Z.
        • Liang G.
        Comparative N-glycoproteomic and phosphoproteomic profiling of human placental plasma membrane between normal and preeclampsia pregnancies with high-resolution mass spectrometry.
        PLoS One. 2013; 8: e80480
        • Wang F.
        • Shi Z.
        • Wang P.
        • You W.
        • Liang G.
        Comparative proteome profile of human placenta from normal and preeclamptic pregnancies.
        PLoS One. 2013; 8: e78025
        • Zhang H.H.
        • Wang Y.P.
        • Chen D.B.
        Analysis of nitroso-proteomes in normotensive and severe preeclamptic human placentas.
        Biol Reprod. 2011; 84: 966-975
        • Dexlin-Mellby L.
        • Sandstrom A.
        • Centlow M.
        • et al.
        Tissue proteome profiling of preeclamptic placenta using recombinant antibody microarrays.
        Proteomics. 2010; 4: 794-807
        • Centlow M.
        • Hansson S.R.
        • Welinder C.
        Differential proteome analysis of the preeclamptic placenta using optimized protein extraction.
        J Biomed Biotechnol. 2010; 2010: 458748
        • Mine K.
        • Katayama A.
        • Matsumura T.
        • et al.
        Proteome analysis of human placentae: pre-eclampsia versus normal pregnancy.
        Placenta. 2007; 28: 676-687
        • Sawicki G.
        • Dakour J.
        • Morrish D.W.
        Functional proteomics of neurokinin B in the placenta indicates a novel role in regulating cytotrophoblast antioxidant defenses.
        Proteomics. 2003; 3: 2044-2051
        • Watanabe H.
        • Hamada H.
        • Yamada N.
        • et al.
        Proteome analysis reveals elevated serum levels of clusterin in patients with preeclampsia.
        Proteomics. 2004; 4: 537-543
        • Blumenstein M.
        • McMaster M.T.
        • Black M.A.
        • et al.
        A proteomic approach identifies early pregnancy biomarkers for preeclampsia: novel linkages between a predisposition to preeclampsia and cardiovascular disease.
        Proteomics. 2009; 9: 2929-2945
        • Park J.
        • Cha D.H.
        • Lee S.J.
        • Kim Y.N.
        • Kim Y.H.
        • Kim K.P.
        Discovery of the serum biomarker proteins in severe preeclampsia by proteomic analysis.
        Exp Mol Med. 2011; 43: 427-435
        • Lee S.M.
        • Park J.S.
        • Norwitz E.R.
        • et al.
        Characterization of discriminatory urinary proteomic biomarkers for severe preeclampsia using SELDI-TOF mass spectrometry.
        J Perinat Med. 2011; 39: 391-396
        • Pecks U.
        • Schutt A.
        • Rower C.
        • et al.
        A mass spectrometric multicenter study supports classification of preeclampsia as heterogeneous disorder.
        Hypertens Pregnancy. 2012; 31: 278-291
        • Kolla V.
        • Jeno P.
        • Moes S.
        • Lapaire O.
        • Hoesli I.
        • Hahn S.
        Quantitative proteomic (iTRAQ) analysis of 1st trimester maternal plasma samples in pregnancies at risk for preeclampsia.
        J Biomed Biotechnol. 2012; 2012: 305964
        • Cusimano M.C.
        • Pudwell J.
        • Roddy M.
        • Jane Cho C.K.
        • Smith GN.
        The maternal health clinic: an initiative for cardiovascular risk identification in women with pregnancy-related complications.
        Am J Obstet Gynecol. 2014; 210: 438.e1-438.e9
        • Lloyd-Jones D.M.
        • Leip E.P.
        • Larson M.G.
        • et al.
        Prediction of lifetime risk for cardiovascular disease by risk factor burden at 50 years of age.
        Circulation. 2006; 113: 791-798
        • Craici I.
        • Wagner S.
        • Garovic V.D.
        Preeclampsia and future cardiovascular risk: formal risk factor or failed stress test?.
        Ther Adv Cardiovasc Dis. 2008; 2: 249-259
        • Agatisa P.K.
        • Ness R.B.
        • Roberts J.M.
        • Costantino J.P.
        • Kuller L.H.
        • McLaughlin M.K.
        Impairment of endothelial function in women with a history of preeclampsia: an indicator of cardiovascular risk.
        Am J Physiol. 2004; 286: H1389-H1393
        • Nisell H.
        • Lintu H.
        • Lunell N.O.
        • Mollerstrom G.
        • Pettersson E.
        Blood pressure and renal function seven years after pregnancy complicated by hypertension.
        Br J Obstet Gynaecol. 1995; 102: 876-881
        • Anagnostopoulos A.K.
        • Tsangaris G.T.
        Proteomics advancements in fetomaternal medicine.
        Clin Biochem. 2013; 46: 487-496
        • Lu F.
        • Longo M.
        • Tamayo E.
        • et al.
        The effect of over-expression of sFlt-1 on blood pressure and the occurrence of other manifestations of preeclampsia in unrestrained conscious pregnant mice.
        Am J Obstet Gynecol. 2007; 196: 396.e1-396.e7
        • Costantine M.M.
        • Tamayo E.
        • Lu F.
        • et al.
        Using pravastatin to improve the vascular reactivity in a mouse model of soluble fms-like tyrosine kinase-1-induced preeclampsia.
        Obstet Gynecol. 2010; 116: 114-120
        • Haeger M.
        • Unander M.
        • Bengtsson A.
        Complement activation in relation to development of preeclampsia.
        Obstet Gynecol. 1991; 78: 46-49
        • Haeger M.
        • Bengtson A.
        • Karlsson K.
        • Heideman M.
        Complement activation and anaphylatoxin (C3a and C5a) formation in preeclampsia and by amniotic fluid.
        Obstet Gynecol. 1989; 73: 551-556
        • Liu C.
        • Zhang N.
        • Yu H.
        • et al.
        Proteomic analysis of human serum for finding pathogenic factors and potential biomarkers in preeclampsia.
        Placenta. 2011; 32: 168-174
        • Blankley R.T.
        • Gaskell S.J.
        • Whetton A.D.
        • Dive C.
        • Baker P.N.
        • Myers J.E.
        A proof-of-principle gel-free proteomics strategy for the identification of predictive biomarkers for the onset of pre-eclampsia.
        BJOG. 2009; 116: 1473-1480
        • Kopeikina L.
        • Kamper E.F.
        • Mantas A.
        • Kremastinos D.T.
        • Stavridis J.
        Plasma tetranectin levels in patients with unstable and stable angina.
        Fibrinolysis Proteol. 1998; 12: 353-359
        • Kamper E.F.
        • Kopeikina L.
        • Mantas A.
        • Stefanadis C.
        • Toutouzas P.
        • Stavridis J.
        Tetranectin levels in patients with acute myocardial infarction and their alterations during thrombolytic treatment.
        Ann Clin Biochem. 1998; 35: 400-407
        • He S.
        • Silveira A.
        • Hamsten A.
        • Blomback M.
        • Bremme K.
        Hemostatic, endothelial and lipoprotein parameters and blood pressure levels in women with a history of preeclampsia.
        Thromb Haemost. 1999; 81: 538-542
        • Freeman D.J.
        • McManus F.
        • Brown E.A.
        • et al.
        Short- and long-term changes in plasma inflammatory markers associated with preeclampsia.
        Hypertension. 2004; 44: 708-714
        • Vitoratos N.
        • Economou E.
        • Iavazzo C.
        • Panoulis K.
        • Creatsas G.
        Maternal serum levels of TNF-alpha and IL-6 long after delivery in preeclamptic and normotensive pregnant women.
        Mediators Inflamm. 2010; 2010: 908649
        • Moreau M.E.
        • Garbacki N.
        • Molinaro G.
        • Brown N.J.
        • Marceau F.
        • Adam A.
        The kallikrein-kinin system: current and future pharmacological targets.
        J Pharmacol Sci. 2005; 99: 6-38
        • Khan F.
        • Belch J.J.
        • MacLeod M.
        • Mires G.
        Changes in endothelial function precede the clinical disease in women in whom preeclampsia develops.
        Hypertension. 2005; 46: 1123-1128
        • Murphy M.S.
        • Vignarajah M.
        • Smith G.N.
        Increased microvascular vasodilation and cardiovascular risk following a pre-eclamptic pregnancy.
        Physiol Rep. 2014; 2
        • Blaauw J.
        • Graaff R.
        • van Pampus M.G.
        • et al.
        Abnormal endothelium-dependent microvascular reactivity in recently preeclamptic women.
        Obstet Gynecol. 2005; 105: 626-632
        • Wong F.
        • Cox B.
        Proteomics analysis of preeclampsia, a systematic review of maternal and fetal compartments.
        J Proteomics Bioinform. 2014; (S10: 001)