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SERPINA5 may promote the development of preeclampsia by disruption of the uPA/uPAR pathway

  • Author Footnotes
    # These authors contributed equally and should be considered as co-first authors.
    Yan Long
    Footnotes
    # These authors contributed equally and should be considered as co-first authors.
    Affiliations
    Department of Laboratory, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China
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  • Author Footnotes
    # These authors contributed equally and should be considered as co-first authors.
    Shanshui Zeng
    Footnotes
    # These authors contributed equally and should be considered as co-first authors.
    Affiliations
    Department of Laboratory, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China
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  • Author Footnotes
    # These authors contributed equally and should be considered as co-first authors.
    Fei Gao
    Footnotes
    # These authors contributed equally and should be considered as co-first authors.
    Affiliations
    Department of Laboratory Medicine Center, Nanfang Hospital, Southern Medical University/The First School of Clinical Medicine, Southern Medical University, Guangzhou, Guangdong, China
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  • Fei Liu
    Affiliations
    Department of Laboratory, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China
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  • Yonggang Zhang
    Affiliations
    Department of Laboratory, Shenzhen Longhua District Central Hospital, Guangdong Medical University, Shenzhen, China
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  • Cheng Zhou
    Affiliations
    Laboratory of Molecular Diagnostics, Southern Medical University Affiliated Maternal & Child Health Hospital of Foshan, Foshan, China
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  • Chunyan Zhu
    Affiliations
    School of Public Health, Guangzhou Medical University, Guangzhou, China
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  • Xueqin Zhao
    Affiliations
    Department of Laboratory, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China
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  • Mengru Han
    Affiliations
    Department of Laboratory, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China
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  • Qiangsheng Gan
    Affiliations
    School of Public Health, Guangzhou Medical University, Guangzhou, China
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  • Weitao Ye
    Affiliations
    School of Public Health, Guangzhou Medical University, Guangzhou, China
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  • Fangling Zeng
    Affiliations
    Department of Gynaecology and Obstetrics, Guangzhou Women and Children's Medical Centre, Guangzhou Medical University, Guangzhou, China
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  • Chunlin Song
    Affiliations
    Laboratory of Molecular Diagnostics, Southern Medical University Affiliated Maternal & Child Health Hospital of Foshan, Foshan, China
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  • Min Jiang
    Correspondence
    Corresponding author at: Gendie E. Lash, Guangzhou Institute of Pediatrics, Guangzhou Women and Children's Medical Centre, Guangzhou Medical University, Guangzhou, 510623, China
    Affiliations
    Department of Laboratory, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China
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  • Gendie E. Lash
    Correspondence
    Corresponding author at: Min Jiang, Department of Laboratory, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, 510623, China
    Affiliations
    Guangzhou Institute of Pediatrics, Guangzhou Women and Children's Medical Centre, Guangzhou Medical University, Guangzhou, China
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  • Hongling Yang
    Correspondence
    Reprint requests: Hongling Yang, Department of Laboratory, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, No. 9 Jinsui Road, Guangzhou 510623, China
    Affiliations
    Department of Laboratory, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China
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  • Author Footnotes
    # These authors contributed equally and should be considered as co-first authors.

      ABSTRACT

      Preeclampsia (PE) is the leading cause of maternal and fetal morbidity or mortality but lacks reliable methods for early diagnosis. In a previous study, serum SERPINA5 levels were higher in women with PE before the clinical manifestation of the disease. This study aimed to evaluate the efficacy of SERPINA5 in predicting PE and investigate its role in trophoblast cell biology. A multicenter, 2-stage observational case-control study was performed to develop and validate an early predictive PE model based on SERPINA5, maternal characteristics, and inflammatory factors. To further understand the relationship between SERPINA5 and PE, SERPINA5 was overexpressed or knocked down in extravillous trophoblast cells (EVT) and a pregnant rat model. After development and initial validation, a model that combined SERPINA5 and inflammatory factors had a high predictive ability for PE before 20 weeks gestation with an AUC of 0.90 (95% CI 0.83–0.96). It also demonstrated that SERPINA5 inhibited primary EVT cell invasion by disrupting the urokinase-type plasminogen activator/urokinase-type plasminogen activator receptor (uPA/uPAR) pathway, in turn, is involved in the development of PE. In vivo experiments also proved that overexpression of SERPINA5 induced a PE-like syndrome (hypertension and proteinuria) in pregnant rats. Therefore, serum SERPINA5 is a promising early biomarker of PE, suggesting that it may be involved in placental development through its action on the uPA/uPAR system prior to the clinical manifestation of PE.

      Abbreviations:

      AUC (area under the curve), CRP (C-reactive protein), EVT (extravillous trophoblast), FER (ferritin), HLA-G (histocompatibility antigen G), IL-6 (interleukin 6), ITGα5 (integrin alpha 5), ITGβ4 (integrin beta 4), ITGα6 (integrin alpha 6), ITGβ1 (integrin beta 1), LPS (lipopolysaccharide), MMP9 (matrix metalloproteinases 9), MMP2 (matrix metalloproteinases 2), PE (preeclampsia), SERPINA5 (serpin family A member 5), SERPINC1 (serum serpin family C member 1), uPA (urokinase-type plasminogen activator), uPAR (urokinase-type plasminogen activator receptor)
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      References

        • Mol BWJ
        • Roberts CT
        • Thangaratinam S
        • Magee LA
        • de Groot CJM
        • Hofmeyr GJ.
        Pre-eclampsia.
        Lancet. 2016; 387: 999-1011
        • Parikh NI
        • Gonzalez J.
        Preeclampsia and hypertension: courting a long while: time to make it official.
        JAMA Intern Med. 2017; 177: 917-918
        • Burton GJ
        • Redman CW
        • Roberts JM
        • Moffett A.
        Pre-eclampsia: pathophysiology and clinical implications.
        BMJ. 2019; 366: l2381
        • American College of Obstetricians and Gynecologists
        ACOG Practice Bulletin No. 202: gestational hypertension and preeclampsia.
        Obstet Gynecol. 2019; 133: 1
        • Brown MA
        • Magee LA
        • Kenny LC
        • et al.
        Hypertensive disorders of pregnancy: ISSHP classification, diagnosis, and management recommendations for international practice.
        Hypertension. 2018; 72: 24-43
        • Zheng Q
        • Yang Y
        • Cui X
        • Zhang D
        • Liu S
        • Yan Q.
        AP1 mediates uPA/uPAR induced FUT4 expression and trophoblast invasion.
        J Cell Biochem. 2018; 119: 6442-6451
        • Verlohren S
        • Dröge LA.
        The diagnostic value of angiogenic and antiangiogenic factors in differential diagnosis of preeclampsia.
        Am J Obstet Gynecol. 2020; 226: S1048-S1058
        • Chaemsaithong P
        • Sahota DS
        • Poon LC.
        First trimester preeclampsia screening and prediction.
        Am J Obstet Gynecol. 2020; 226: S1071-S1097
        • Bian X
        • Biswas A
        • Huang X
        • et al.
        Short-term prediction of adverse outcomes using the sFlt-1 (soluble fms-like tyrosine kinase 1)/PlGF (placental growth factor) ratio in Asian women with suspected preeclampsia.
        Hypertension. 2019; 74: 164-172
        • Fantone S
        • Mazzucchelli R
        • Giannubilo SR
        • Ciavattini A
        • Marzioni D
        • Tossetta G.
        AT-rich interactive domain 1A protein expression in normal and pathological pregnancies complicated by preeclampsia.
        Histochem Cell Biol. 2020; 154: 339-346
        • Opichka MA
        • Rappelt MW
        • Gutterman DD
        • Grobe JL
        • McIntosh JJ.
        Vascular dysfunction in preeclampsia.
        Cells. 2021; 10: 3055
        • Lash GE
        • Otun HA
        • Innes BA
        • Bulmer JN
        • Searle RF
        • Robson SC.
        Inhibition of trophoblast cell invasion by TGFB1, 2, and 3 is associated with a decrease in active proteases.
        Biol Reprod. 2005; 73: 374-381
        • Abbas Y
        • Turco MY
        • Burton GJ
        • Moffett A.
        Investigation of human trophoblast invasion in vitro.
        Hum Reprod Update. 2020; 26: 501-513
        • Zhang Y
        • Zhang Y
        • Zhao L
        • Shi J
        • Yang H.
        Plasma SerpinA5 in conjunction with uterine artery pulsatility index and clinical risk factor for the early prediction of preeclampsia.
        PLoS One. 2021; 16e0258541
        • Yang H
        • Geiger M.
        Cell penetrating SERPINA5 (ProteinC inhibitor, PCI): more questions than answers.
        Semin Cell Dev Biol. 2017; 62: 187-193
        • Wahlmüller FC
        • Yang H
        • Furtmüller M
        • Geiger M.
        Regulation of the extracellular SERPINA5 (protein C inhibitor) penetration through cellular membranes.
        Adv Exp Med Biol. 2017; 966: 93-101
        • Suzuki K.
        Protein C inhibitor (PAI-3): structure and multi-function.
        Fibrinolysis Proteolysis. 2000; 14: 133-145
        • Bijsmans ITGW
        • Smits KM
        • de Graeff P
        • et al.
        Loss of SerpinA5 protein expression is associated with advanced-stage serous ovarian tumors.
        Mod Pathol. 2011; 24: 463-470
        • Jing Y
        • Jia D
        • Wong CM
        • et al.
        SERPINA5 inhibits tumor cell migration by modulating the fibronectin-integrin β1 signaling pathway in hepatocellular carcinoma.
        Mol Oncol. 2014; 8: 366-377
        • Zeng S
        • Han M
        • Jiang M
        • et al.
        Serum complement proteomics reveal biomarkers for hypertension disorder of pregnancy and the potential role of clusterin.
        Reprod Biol Endocrinol. 2021; 19: 56
        • Zeng S
        • Pan Y
        • Liu F
        • et al.
        Role of clusterin in the regulation of trophoblast development and preeclampsia.
        Biochem Biophys Res Commun. 2021; 583: 128-134
        • Graham CH
        • Hawley TS
        • Hawley RG
        • et al.
        Establishment and characterization of first trimester human trophoblast cells with extended lifespan.
        Exp Cell Res. 1993; 206: 204-211
        • Jiang M
        • Lash GE
        • Zeng S
        • et al.
        Differential expression of serum proteins before 20 weeks gestation in women with hypertensive disorders of pregnancy: a potential role for SH3BGRL3.
        Placenta. 2021; 104: 20-30
        • Lash GE
        • Otun HA
        • Innes BA
        • Bulmer JN
        • Searle RF
        • Robson SC.
        Low oxygen concentrations inhibit trophoblast cell invasion from early gestation placental explants via alterations in levels of the urokinase plasminogen activator system.
        Biol Reprod. 2006; 74: 403-409
        • Zhang Y
        • Yang H
        • Zhang Y
        • Shi J
        • Chen R
        • Xiao X.
        CircSFXN1 regulates the behaviour of trophoblasts and likely mediates preeclampsia.
        Placenta. 2020; 101: 115-123
        • Kang YS
        • Lee MH
        • Song HK
        • et al.
        CCR2 antagonism improves insulin resistance, lipid metabolism, and diabetic nephropathy in type 2 diabetic mice.
        Kidney Int. 2010; 78: 883-894
        • Rebelo F
        • Schlüssel MM
        • Vaz JS
        • et al.
        C-reactive protein and later preeclampsia: systematic review and meta-analysis taking into account the weight status.
        J Hypertens. 2013; 31: 16-26
        • Mannaerts D
        • Faes E
        • Cos P
        • et al.
        Oxidative stress in healthy pregnancy and preeclampsia is linked to chronic inflammation, iron status and vascular function.
        PLoS One. 2018; 13e0202919
        • Lau SY
        • Guild SJ
        • Barrett CJ
        • et al.
        Tumor necrosis factor-alpha, interleukin-6, and interleukin-10 levels are altered in preeclampsia: a systematic review and meta-analysis.
        Am J Reprod Immunol. 2013; 70: 412-427
        • Liu J
        • Chakraborty C
        • Graham CH
        • Barbin YP
        • Dixon SJ
        • Lala PK.
        Noncatalytic domain of uPA stimulates human extravillous trophoblast migration by using phospholipase C, phosphatidylinositol 3-kinase and mitogen-activated protein kinase.
        Exp Cell Res. 2003; 286: 138-151
        • de Rijk EPCT
        • van Esch E
        • Flik G.
        Pregnancy dating in the rat: placental morphology and maternal blood parameters.
        Toxicol Pathol. 2002; 30: 271-282
        • Henderson JT
        • Thompson JH
        • Burda BU
        • Cantor A.
        Preeclampsia screening: evidence report and systematic review for the US Preventive Services Task Force.
        JAMA. 2017; 317: 1668-1683
        • Rasanen J
        • Girsen A
        • Lu X
        • et al.
        Comprehensive maternal serum proteomic profiles of preclinical and clinical preeclampsia.
        J Proteome Res. 2010; 9: 4274-4281
        • Myers JE
        • Tuytten R
        • Thomas G
        • et al.
        Integrated proteomics pipeline yields novel biomarkers for predicting preeclampsia.
        Hypertension. 2013; 61: 1281-1288
        • Warg LA
        • Oakes JL
        • Burton R
        • et al.
        The role of the E2F1 transcription factor in the innate immune response to systemic LPS.
        Am J Physiol Lung Cell Mol Physiol. 2012; 303: L391-L400
        • Chen J
        • Khalil RA.
        Matrix metalloproteinases in normal pregnancy and preeclampsia.
        Prog Mol Biol Transl Sci. 2017; 148: 87-165
        • Aplin JD.
        Expression of integrin alpha 6 beta 4 in human trophoblast and its loss from extravillous cells.
        Placenta. 1993; 14: 203-215
        • Aplin JD
        • Haigh T
        • Jones CJ
        • Church HJ
        • Vićovac L.
        Development of cytotrophoblast columns from explanted first-trimester human placental villi: role of fibronectin and integrin alpha5beta1.
        Biol Reprod. 1999; 60: 828-838
        • Yamamoto E
        • Ino K
        • Miyoshi E
        • et al.
        N-acetylglucosaminyltransferase V regulates extravillous trophoblast invasion through glycosylation of alpha5beta1 integrin.
        Endocrinology. 2009; 150: 990-999
        • Zhang Y
        • Yang H
        • Zhang Y
        • Shi J
        • Chen R.
        circCRAMP1L is a novel biomarker of preeclampsia risk and may play a role in preeclampsia pathogenesis via regulation of the MSP/RON axis in trophoblasts.
        BMC Pregnancy Childbirth. 2020; 20: 652
        • Cater JH
        • Kumita JR
        • Zeineddine Abdallah R
        • et al.
        Human pregnancy zone protein stabilizes misfolded proteins including preeclampsia- and Alzheimer's-associated amyloid beta peptide.
        Proc Natl Acad Sci U S A. 2019; 116: 6101-6110
        • Furukawa S
        • Tsuji N
        • Sugiyama A.
        Morphology and physiology of rat placenta for toxicological evaluation.
        J Toxicol Pathol. 2019; 32: 1-17
        • Silva JF
        • Serakides R.
        Intrauterine trophoblast migration: a comparative view of humans and rodents.
        Cell Adhes Migr. 2016; 10: 88-110
        • Hayes EK
        • Tessier DR
        • Percival ME
        • et al.
        Trophoblast invasion and blood vessel remodeling are altered in a rat model of lifelong maternal obesity.
        Reprod Sci. 2014; 21: 648-657
        • 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: 649-658
        • Moghaddas Sani H
        • Zununi Vahed S
        • Ardalan M
        Preeclampsia: a close look at renal dysfunction.
        Biomed Pharmacother. 2019; 109: 408-416
        • Elisen MG
        • von dem Borne PA
        • Bouma BN
        • Meijers JC.
        Protein C inhibitor acts as a procoagulant by inhibiting the thrombomodulin-induced activation of protein C in human plasma.
        Blood. 1998; 91: 1542-1547