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)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 accessOne-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:
Subscribe to Translational ResearchAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- Pre-eclampsia.Lancet. 2016; 387: 999-1011
- Preeclampsia and hypertension: courting a long while: time to make it official.JAMA Intern Med. 2017; 177: 917-918
- Pre-eclampsia: pathophysiology and clinical implications.BMJ. 2019; 366: l2381
- ACOG Practice Bulletin No. 202: gestational hypertension and preeclampsia.Obstet Gynecol. 2019; 133: 1
- Hypertensive disorders of pregnancy: ISSHP classification, diagnosis, and management recommendations for international practice.Hypertension. 2018; 72: 24-43
- AP1 mediates uPA/uPAR induced FUT4 expression and trophoblast invasion.J Cell Biochem. 2018; 119: 6442-6451
- The diagnostic value of angiogenic and antiangiogenic factors in differential diagnosis of preeclampsia.Am J Obstet Gynecol. 2020; 226: S1048-S1058
- First trimester preeclampsia screening and prediction.Am J Obstet Gynecol. 2020; 226: S1071-S1097
- 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
- AT-rich interactive domain 1A protein expression in normal and pathological pregnancies complicated by preeclampsia.Histochem Cell Biol. 2020; 154: 339-346
- Vascular dysfunction in preeclampsia.Cells. 2021; 10: 3055
- Inhibition of trophoblast cell invasion by TGFB1, 2, and 3 is associated with a decrease in active proteases.Biol Reprod. 2005; 73: 374-381
- Investigation of human trophoblast invasion in vitro.Hum Reprod Update. 2020; 26: 501-513
- Plasma SerpinA5 in conjunction with uterine artery pulsatility index and clinical risk factor for the early prediction of preeclampsia.PLoS One. 2021; 16e0258541
- Cell penetrating SERPINA5 (ProteinC inhibitor, PCI): more questions than answers.Semin Cell Dev Biol. 2017; 62: 187-193
- Regulation of the extracellular SERPINA5 (protein C inhibitor) penetration through cellular membranes.Adv Exp Med Biol. 2017; 966: 93-101
- Protein C inhibitor (PAI-3): structure and multi-function.Fibrinolysis Proteolysis. 2000; 14: 133-145
- Loss of SerpinA5 protein expression is associated with advanced-stage serous ovarian tumors.Mod Pathol. 2011; 24: 463-470
- SERPINA5 inhibits tumor cell migration by modulating the fibronectin-integrin β1 signaling pathway in hepatocellular carcinoma.Mol Oncol. 2014; 8: 366-377
- Serum complement proteomics reveal biomarkers for hypertension disorder of pregnancy and the potential role of clusterin.Reprod Biol Endocrinol. 2021; 19: 56
- Role of clusterin in the regulation of trophoblast development and preeclampsia.Biochem Biophys Res Commun. 2021; 583: 128-134
- Establishment and characterization of first trimester human trophoblast cells with extended lifespan.Exp Cell Res. 1993; 206: 204-211
- 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
- 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
- CircSFXN1 regulates the behaviour of trophoblasts and likely mediates preeclampsia.Placenta. 2020; 101: 115-123
- CCR2 antagonism improves insulin resistance, lipid metabolism, and diabetic nephropathy in type 2 diabetic mice.Kidney Int. 2010; 78: 883-894
- C-reactive protein and later preeclampsia: systematic review and meta-analysis taking into account the weight status.J Hypertens. 2013; 31: 16-26
- Oxidative stress in healthy pregnancy and preeclampsia is linked to chronic inflammation, iron status and vascular function.PLoS One. 2018; 13e0202919
- 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
- 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
- Pregnancy dating in the rat: placental morphology and maternal blood parameters.Toxicol Pathol. 2002; 30: 271-282
- Preeclampsia screening: evidence report and systematic review for the US Preventive Services Task Force.JAMA. 2017; 317: 1668-1683
- Comprehensive maternal serum proteomic profiles of preclinical and clinical preeclampsia.J Proteome Res. 2010; 9: 4274-4281
- Integrated proteomics pipeline yields novel biomarkers for predicting preeclampsia.Hypertension. 2013; 61: 1281-1288
- 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
- Matrix metalloproteinases in normal pregnancy and preeclampsia.Prog Mol Biol Transl Sci. 2017; 148: 87-165
- Expression of integrin alpha 6 beta 4 in human trophoblast and its loss from extravillous cells.Placenta. 1993; 14: 203-215
- Development of cytotrophoblast columns from explanted first-trimester human placental villi: role of fibronectin and integrin alpha5beta1.Biol Reprod. 1999; 60: 828-838
- N-acetylglucosaminyltransferase V regulates extravillous trophoblast invasion through glycosylation of alpha5beta1 integrin.Endocrinology. 2009; 150: 990-999
- 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
- 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
- Morphology and physiology of rat placenta for toxicological evaluation.J Toxicol Pathol. 2019; 32: 1-17
- Intrauterine trophoblast migration: a comparative view of humans and rodents.Cell Adhes Migr. 2016; 10: 88-110
- Trophoblast invasion and blood vessel remodeling are altered in a rat model of lifelong maternal obesity.Reprod Sci. 2014; 21: 648-657
- 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
- Preeclampsia: a close look at renal dysfunction.Biomed Pharmacother. 2019; 109: 408-416
- Protein C inhibitor acts as a procoagulant by inhibiting the thrombomodulin-induced activation of protein C in human plasma.Blood. 1998; 91: 1542-1547
Article info
Publication history
Published online: June 14, 2022
Accepted:
June 10,
2022
Received in revised form:
May 24,
2022
Received:
March 1,
2022
Editor: Mr. M. FranklinIdentification
Copyright
© 2022 Elsevier Inc. All rights reserved.
