Skip to main content

Advertisement

SpringerLink
Log in

Maternal plasma TIMP-4 levels combined with clinical risk factors for the early prediction of pregnancy-induced hypertension

  • Maternal-Fetal Medicine
  • Published:
Archives of Gynecology and Obstetrics Aims and scope Submit manuscript

Abstract

Objective

The objective of this study was to create a model for early predicting pregnancy-induced hypertension (PIH) using plasma markers and clinical risk factors.

Methods

A nested case–control study was performed at the Laboratory Department of Guangzhou Women and Children’s Medical Center. From a prospective cohort of tens of thousands of unselected women with singleton pregnancies at 8–20 weeks gestation, maternal plasma samples were obtained from 73 women who subsequently developed PIH (PIH group) and 146 gestational age- and maternal age-matched women with normotensive pregnancies (control group). Proteins extracted from the plasma samples were screened by microchip and verified by ELISA. Clinical risk factor data were analyzed retrospectively.

Results

Compared to the control group, high concentrations of tissue inhibitor of metalloproteinase-4 (TIMP-4) were found in women with PIH (P = 0.000). Univariate risk factor analysis identified three variables with significant differences between the groups: family history of PIH (P = 0.031), body mass index (BMI; P < 0.001), and non-glucose-6-phosphate dehydrogenase deficiency-induced anemia (P < 0.027). Multiple regression analyses revealed a significant relationship of PIH with TIMP-4 levels, BMI, and family history (combined area under the receiver operating characteristic curve = 0.820).

Conclusion

Upregulation of plasma TIMP-4 might contribute to PIH processes. Potential risk factors of this disease may include a family history of PIH and BMI. The combination of TIMP-4 levels and these risk factors may have some predictive values for PIH. Future multicenter studies including greater numbers of samples, analyzed proteins, and risk factors are needed to obtain a higher predictive value of the model for the clinical diagnosis of PIH.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

Abbreviations

PIH:

Pregnancy-induced hypertension

TIMP:

Tissue inhibitor of metalloproteinase

BMP-5:

Bone morphogenetic protein-5

MMP:

Matrix metalloproteinase

ECM:

Extracellular matrix

BMI:

Body mass index

G6PD:

Glucose-6-phosphate dehydrogenase

ROC:

Receiver operating characteristic

AUC:

Area under the ROC curve

GA:

Gestational age

MA:

Maternal age

PPV:

Positive predictive value

NPV:

Negative predictive value

PLR:

Positive likelihood ratio

NLR:

Negative likelihood ratio

MT1:

Membrane type 1

References

  1. Noguchi J, Tanaka H, Koyanagi A et al (2014) Three-dimensional power Doppler indices at 18–22 weeks’ gestation for prediction of fetal growth restriction or pregnancy-induced hypertension. Arch Gynecol Obstet. doi:10.1007/s00404-014-3603-z

  2. Rahimi Z, Kazemian L, Malek-Khosravi S et al (2015) Matrix metalloproteinase-7 A-181G and its interaction with matrix metalloproteinase-9 C-1562T polymorphism in preeclamptic patients: association with malondialdehyde level and severe preeclampsia. Arch Gynecol Obstet 291:45–51

    Article  CAS  PubMed  Google Scholar 

  3. Palei AC, Sandrim VC, Amaral LM et al (2012) Association between matrix metalloproteinase (MMP)-2 polymorphisms and MMP-2 levels in hypertensive disorders of pregnancy. Exp Mol Pathol 92:217–221

    Article  CAS  PubMed  Google Scholar 

  4. Romao M, Weel IC, Lifshitz SJ et al (2014) Elevated hyaluronan and extracellular matrix metalloproteinase inducer levels in women with preeclampsia. Arch Gynecol Obstet 289:575–579

    Article  CAS  PubMed  Google Scholar 

  5. Tayebjee MH, Karalis I, Nadar SK et al (2005) Circulating matrix metalloproteinase-9 and tissue inhibitors of metalloproteinases-1 and -2 levels in gestational hypertension. Am J Hypertens 18:325–329

    Article  CAS  PubMed  Google Scholar 

  6. Sheppard SJ, Khalil RA (2010) Risk factors and mediators of the vascular dysfunction associated with hypertension in pregnancy. Cardiovasc Hematol Disord Drug Targets 10:33–52

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  7. Montagnana M, Lippi G, Albiero A, Scevarolli S, Salvagno GL et al (2009) Evaluation of metalloproteinases 2 and 9 and their inhibitors in physiologic and pre-eclamptic pregnancy. J Clin Lab Anal 23:88–92

    Article  CAS  PubMed  Google Scholar 

  8. Anacker J, Segerer SE, Hagemann C, Feix S, Kapp M et al (2011) Human decidua and invasive trophoblasts are rich sources of nearly all human matrix metalloproteinases. Mol Hum Reprod 17:637–652

    Article  CAS  PubMed  Google Scholar 

  9. Karthikeyan VJ, Lane DA, Beevers DG, Lip GY, Blann AD (2013) Matrix metalloproteinases and their tissue inhibitors in hypertension-related pregnancy complications. J Hum Hypertens 27:72–78

    Article  CAS  PubMed  Google Scholar 

  10. Xiang Y, Zhang X, Li Q, Xu J, Zhou X et al (2013) Promoter hypomethylation of TIMP3 is associated with pre-eclampsia in a Chinese population. Mol Hum Reprod 19:153–159

    Article  CAS  PubMed  Google Scholar 

  11. Roberts JM, Pearson G, Cutler J et al (2003) Summary of the NHLBI Working Group on research on hypertension during pregnancy. Hypertension 41:437–445

    Article  CAS  PubMed  Google Scholar 

  12. Lockwood CJ, Oner C, Uz YH, Kayisli UA, Huang SJ et al (2008) Matrix metalloproteinase 9 (MMP9) expression in preeclamptic decidua and MMP9 induction by tumor necrosis factor alpha and interleukin 1 beta in human first trimester decidual cells. Biol Reprod 78:1064–1072

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  13. Raffetto JD, Khalil RA (2008) Matrix metalloproteinases and their inhibitors in vascular remodeling and vascular disease. Biochem Pharmacol 75:346–359

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  14. Galewska Z, Romanowicz L, Jaworski S, Bankowski E (2008) Gelatinase matrix metalloproteinase (MMP)-2 and MMP-9 of the umbilical cord blood in preeclampsia. Clin Chem Lab Med 46:517–522

    Article  CAS  PubMed  Google Scholar 

  15. Lee SB, Wong AP, Kanasaki K, Xu Y, Shenoy VK et al (2010) Preeclampsia: 2-methoxyestradiol induces cytotrophoblast invasion and vascular development specifically under hypoxic conditions. Am J Pathol 176:710–720

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  16. Palei AC, Sandrim VC, Amaral LM, Machado JS, Cavalli RC et al (2012) Matrix metalloproteinase-9 polymorphisms affect plasma MMP-9 levels and antihypertensive therapy responsiveness in hypertensive disorders of pregnancy. Pharmacogenomics J 12:489–498

    Article  CAS  PubMed  Google Scholar 

  17. Hilska M, Roberts PJ, Collan YU, Laine VJ, Kossi J et al (2007) Prognostic significance of matrix metalloproteinases-1, -2, -7 and -13 and tissue inhibitors of metalloproteinases-1, -2, -3 and -4 in colorectal cancer. Int J Cancer 121:714–723

    Article  CAS  PubMed  Google Scholar 

  18. Lee S, Desai KK, Iczkowski KA, Newcomer RG, Wu KJ et al (2006) Coordinated peak expression of MMP-26 and TIMP-4 in preinvasive human prostate tumor. Cell Res 16:750–758

    Article  CAS  PubMed  Google Scholar 

  19. Webb CS, Bonnema DD, Ahmed SH, Leonardi AH, McClure CD et al (2006) Specific temporal profile of matrix metalloproteinase release occurs in patients after myocardial infarction: relation to left ventricular remodeling. Circulation 114:1020–1027

    Article  CAS  PubMed  Google Scholar 

  20. Zavadzkas JA, Stroud RE, Bouges S, Mukherjee R, Jones JR et al (2014) Targeted overexpression of tissue inhibitor of matrix metalloproteinase-4 modifies post-myocardial infarction remodeling in mice. Circ Res 114:1435–1445

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  21. Cecchetti L, Tolley ND, Michetti N, Bury L, Weyrich AS et al (2011) Megakaryocytes differentially sort mRNAs for matrix metalloproteinases and their inhibitors into platelets: a mechanism for regulating synthetic events. Blood 118:1903–1911

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  22. Li D (2006) Peaking of MMP-26 and TIMP-4 marks invasive transition in prostate cancer. Cell Res 16:741

    Article  CAS  PubMed  Google Scholar 

  23. Yang Q, Wang HX, Zhao YG, Lin HY, Zhang H et al (2006) Expression of tissue inhibitor of metalloproteinase-4 (TIMP-4) in endometrium and placenta of rhesus monkey (Macaca mulatta) during early pregnancy. Life Sci 78:2804–2811

    Article  CAS  PubMed  Google Scholar 

  24. Zhang J, Cao YJ, Zhao YG, Sang QX, Duan EK (2002) Expression of matrix metalloproteinase-26 and tissue inhibitor of metalloproteinase-4 in human normal cytotrophoblast cells and a choriocarcinoma cell line, JEG-3. Mol Hum Reprod 8:659–666

    Article  CAS  PubMed  Google Scholar 

  25. Pilka R, Noskova V, Domanski H, Andersson C, Hansson S et al (2006) Endometrial TIMP-4 mRNA is expressed in the stroma, while TIMP-4 protein accumulates in the epithelium and is released to the uterine fluid. Mol Hum Reprod 12:497–503

    Article  CAS  PubMed  Google Scholar 

  26. Bu SM, Hu Z, Zhang F, Duan EK (2008) Changing trends of the expression of TIMP-4 in mouse ovary during pregnant and postpartum period. Zhongguo Ying Yong Sheng Li Xue Za Zhi 24:248–252

    CAS  PubMed  Google Scholar 

  27. Singh M, Kindelberger D, Nagymanyoki Z, Ng SW, Quick CM et al (2011) Matrix metalloproteinases and their inhibitors and inducer in gestational trophoblastic diseases and normal placenta. Gynecol Oncol 122:178–182

    Article  CAS  PubMed  Google Scholar 

  28. Zhang J, Zhao YG, Cao YJ, Sang QX, Duan EK (2003) Expression and implications of tissue inhibitor of metalloproteinases-4 in mouse embryo. Mol Hum Reprod 9:143–149

    Article  PubMed  Google Scholar 

  29. Hulboy DL, Rudolph LA, Matrisian LM (1997) Matrix metalloproteinases as mediators of reproductive function. Mol Hum Reprod 3:27–45

    Article  CAS  PubMed  Google Scholar 

  30. Riley SC, Leask R, Chard T, Wathen NC, Calder AA et al (1999) Secretion of matrix metalloproteinase-2, matrix metalloproteinase-9 and tissue inhibitor of metalloproteinases into the intrauterine compartments during early pregnancy. Mol Hum Reprod 5:376–381

    Article  CAS  PubMed  Google Scholar 

  31. Ab HJ, Mohtarrudin N, Osman M, Andi AA, Wan HW et al (2012) Matrix metalloproteinase-9 and tissue inhibitors of metalloproteinases 1 and 2 as potential biomarkers for gestational hypertension. Singapore Med J 53:681–683

    Google Scholar 

  32. Bigg HF, Morrison CJ, Butler GS, Bogoyevitch MA, Wang Z et al (2001) Tissue inhibitor of metalloproteinases-4 inhibits but does not support the activation of gelatinase A via efficient inhibition of membrane type 1-matrix metalloproteinase. Cancer Res 61:3610–3618

    CAS  PubMed  Google Scholar 

  33. Illera MJ, Cullinan E, Gui Y, Yuan L, Beyler SA et al (2000) Blockade of the alpha (v) beta (3) integrin adversely affects implantation in the mouse. Biol Reprod 62:1285–1290

    Article  CAS  PubMed  Google Scholar 

  34. Liu YE, Wang M, Greene J, Su J, Ullrich S et al (1997) Preparation and characterization of recombinant tissue inhibitor of metalloproteinase 4 (TIMP-4). J Biol Chem 272:20479–20483

    Article  CAS  PubMed  Google Scholar 

  35. Hernandez-Barrantes S, Shimura Y, Soloway PD, Sang QA, Fridman R (2001) Differential roles of TIMP-4 and TIMP-2 in pro-MMP-2 activation by MT1-MMP. Biochem Biophys Res Commun 281:126–130

    Article  CAS  PubMed  Google Scholar 

  36. English JL, Kassiri Z, Koskivirta I, Atkinson SJ, Di Grappa M et al (2006) Individual Timp deficiencies differentially impact pro-MMP-2 activation. J Biol Chem 281:10337–10346

    Article  CAS  PubMed  Google Scholar 

  37. Rosser ML, Katz NT (2013) Preeclampsia: an obstetrician’s perspective. Adv Chronic Kidney Dis 20:287–296

    Article  PubMed  Google Scholar 

  38. Walker JJ (2000) Pre-eclampsia. Lancet 356:1260–1265

    Article  CAS  PubMed  Google Scholar 

  39. Duckitt K, Harrington D (2005) Risk factors for pre-eclampsia at antenatal booking: systematic review of controlled studies. BMJ 330:565

    Article  PubMed Central  PubMed  Google Scholar 

  40. Arulkumaran N, Lightstone L (2013) Severe pre-eclampsia and hypertensive crises. Best Pract Res Clin Obstet Gynaecol 27:877–884

    Article  CAS  PubMed  Google Scholar 

  41. Sibai BM, Lindheimer M, Hauth J, Caritis S, VanDorsten P et al (1998) Risk factors for preeclampsia, abruptio placentae, and adverse neonatal outcomes among women with chronic hypertension. National Institute of Child Health and Human Development Network of Maternal-Fetal Medicine Units. N Engl J Med 339:667–671

    Article  CAS  PubMed  Google Scholar 

  42. Magnussen EB, Vatten LJ, Lund-Nilsen TI, Salvesen KA, Davey SG et al (2007) Prepregnancy cardiovascular risk factors as predictors of pre-eclampsia: population based cohort study. BMJ 335:978

    Article  CAS  PubMed Central  PubMed  Google Scholar 

Download references

Acknowledgments

We thank the statistician Mr. Lin for statistical support. We gratefully acknowledge nurse Mrs. Wu for collecting prenatal and postpartum data, and the Medical Records Room for supplying case information. We appreciate senior sister and brother apprentice for collecting the blood samples.

Conflict of interest

There are not any conflicts ofinterest among authors or others.

Author information

Authors and Affiliations

  1. Laboratory Department, Guangzhou Women and Children Medical Center, Guangzhou Medical University, Guangzhou, China

    Yonggang Zhang, Qinling Ma, Hongling Yang, Yan Long & Chen Zhou

  2. Laboratory Department, The 324th Hospital of Third Military Medical University, Chongqing, China

    Xingxing Liu

Authors
  1. Yonggang Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Qinling Ma
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hongling Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yan Long
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Xingxing Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Chen Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Hongling Yang.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zhang, Y., Ma, Q., Yang, H. et al. Maternal plasma TIMP-4 levels combined with clinical risk factors for the early prediction of pregnancy-induced hypertension. Arch Gynecol Obstet 292, 1043–1050 (2015). https://doi.org/10.1007/s00404-015-3753-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00404-015-3753-7

Keywords

Search

Navigation