Decreased expression of annexin A2 and loss of its association with vascular endothelial growth factor leads to the deficient trophoblastic invasion in preeclampsia
-
Komal Ruikar
, Udupi Shastry Dinesh
Abstract
Objectives
Preeclampsia (PE) remains the major cause for maternal and foetal mortality and morbidity. Invasion of endovascular trophoblast and remodelling of spiral artery are crucial actions of normal placental development. Non-fulfilment of these processes plays a leading role in the development of preeclampsia. Vascular endothelial growth factor (VEGF) is produced by extravillous trophoblastic tissue and decidual cell population is a well-known angiogenic growth which plays a fundamental role in placental pathogenesis of PE. Annexin A2 (ANXA2) is a profibrinolytic protein receptor required for plasminolysis, which is an important step in the formation of new blood vessel along with VEGF. Role of ANXA2 is poorly studied in context with human reproductive disease like preeclampsia. The purpose of the present study is to examine the expression and association of VEGF and ANXA2 in the term placentas of pregnancies with and without PE.
Methods
The study group comprised of placental tissues procured from gestations with PE (n=30) and without (n=20) PE. The expression of VEGF and ANXA2 in the placental villous tissue was evaluated quantitatively by means of IHC, western blotting and reverse transcriptase-polymerase chain reaction (RT-PCR).
Results
Our IHC, western blotting and RT-PCR analysis illustrated the significant decrease in the expression of VEGF and ANXA2 in PE group compared with the normotensive control group (p<0.005). We observed statistically significant positive correlation among the expression of ANXA2 and VEGF in placentas of normotensive control group (p<0.0001).
Conclusions
The diminished expression of VEGF and ANXA2 in placenta may be associated with the defective angiogenesis and which may possibly play a vital role in PE pathogenesis.
Acknowledgments
The authors would like to acknowledge the help of Mr. Gururaj and Mr Aslam for technical assistance.
-
Research funding: None declared.
-
Author contributions: All authors have accepted responsibility for the entire content of this manuscript and approved its submission. Conceived the idea and designed the experiments: KR and PKS; helped in clinical sample; Collection and correlated the clinical relevance to the study: AN, and VK; Performed the experiments: KR, RS, SE, and AB; Analysed the data (pathology): USD. Analysed the data (statistical analysis): VK, KR, PKS, PP, and AB; Manuscript preparation: PP and PKS; Supervised the overall study: PKS and MA.
-
Competing interests: Authors state no conflict of interest.
-
Informed consent: Informed consent was obtained from all individuals included in this study.
-
Ethical approval: The study was conducted following informed consent and was approved by the Ethical Committees of SDM College of Medical Sciences & Hospital, Dharwad, Karnataka, India (SDM IEC: 0748: 2016).
References
1. Ahmed, R, Dunford, J, Mehran, R, Robson, S, Kunadian, V. Pre-eclampsia and future cardiovascular risk among women. J Am Coll Cardiol 2014;63:1815–22. https://doi.org/10.1016/j.jacc.2014.02.529.Search in Google Scholar
2. Lyall, F. The human placental bed revisited. Placenta 2002;23:555–62. https://doi.org/10.1053/plac.2002.0850.Search in Google Scholar
3. Kim, YM, Bujold, E, Chaiworapongsa, T, Gomez, R, Yoon, BH, Thaler, HT, et al.. Failure of physiologic transformation of the spiral arteries in patients with preterm labor and intact membranes. Am J Obstet Gynecol 2003;189:1063–9. https://doi.org/10.1067/s0002-9378(03)00838-x.Search in Google Scholar
4. Lash, GE, Cartwright, JE, Whitley, GS, Trew, AJ, Baker, PN. The effects of angiogenic growth factors on extravillous trophoblast invasion and motility. Placenta 1999;20:661–7. https://doi.org/10.1053/plac.1999.0427.Search in Google Scholar
5. Fitzpatrick, TE, Lash, GE, Yanaihara, A, Charnock-Jones, DS, Macdonald-Goodfellow, SK, Graham, CH. Inhibition of breast carcinoma and trophoblast cell invasiveness by vascular endothelial growth factor. Exp Cell Res 2003;283:247–55. https://doi.org/10.1016/s0014-4827(02)00044-7.Search in Google Scholar
6. Distler, JH, Hirth, A, Kurowska-Stolarska, M, Gay, RE, Gay, S, Distler, O. Angiogenic and angiostatic factors in the molecular control of angiogenesis. Q J Nucl Med 2003;47:149–61.Search in Google Scholar
7. Schiessl, B, Innes, BA, Bulmer, JN, Otun, HA, Chadwick, TJ, Robson, SC, et al.. Localization of angiogenic growth factors and their receptors in the human placental bed throughout normal human pregnancy. Placenta 2009;30:79–87. https://doi.org/10.1016/j.placenta.2008.10.004.Search in Google Scholar
8. Zhou, Y, McMaster, M, Woo, K, Janatpour, M, Perry, J, Karpanen, T, et al.. Vascular endothelial growth factor ligands and receptors that regulate human cytotrophoblast survival are dysregulated in severe preeclampsia and hemolysis, elevated liver enzymes, and low platelets syndrome. Am J Pathol 2002;160:1405–23. https://doi.org/10.1016/s0002-9440(10)62567-9.Search in Google Scholar
9. Plaisier, M, Rodrigues, S, Willems, F, Koolwijk, P, van Hinsbergh, VWM, Helmerhorst, FM. Different degrees of vascularisation and their relationship to the expression of vascular endothelial growth factor, placental growth factor, angiopoietins, and their receptors in first-trimester decidual tissues. Fertil Steril 2007;88:176–87. https://doi.org/10.1016/j.fertnstert.2006.11.102.Search in Google Scholar PubMed
10. Kim, J, Hajjar, KA. Annexin II: a plasminogen-plasminogen activator coreceptor. Front Biosci 2002;1:341–8.10.2741/kimSearch in Google Scholar PubMed
11. Hajjar, KA, Menell, JS. Annexin II: a novel mediator of cell surface plasmin generation. Ann N Y Acad Sci 1997;15:337–49. https://doi.org/10.1111/j.1749-6632.1997.tb52013.x.Search in Google Scholar PubMed
12. Zhao, SH, Huang, LN, Wu, JH, Zhang, Y, Pan, DY, Liu, X. Vascular endothelial growth factor up regulates expression of annexin A2 in vitro and in a mouse model of ischemic retinopathy. Mol Vis 2009;15:1231–42.Search in Google Scholar
13. Shetty, PK, Thamake, SI, Biswas, S, Johansson, SL, Vishwanatha, JK. Reciprocal regulation of annexin A2 and EGFR with Her-2 in Her-2 negative and herceptin-resistant breast cancer. PloS One 2012;7:e44299. https://doi.org/10.1371/journal.pone.0044299.Search in Google Scholar
14. Milovanov, AP, Sidorova, IS, Solonitsyn, AN, Borovkova, EI. Immunohistochemical evaluation of the distribution of vascular endothelial growth factor in the placenta, placental bed in normal pregnancy and in women with preeclampsia. Arkh Patol 2008;70:12–5.Search in Google Scholar
15. Cirpan, T, Akercan, F, Terek, MC, Kazandi, M, Ozcakir, HT, Giray, G, et al.. Evaluation of VEGF in placental bed biopsies from preeclamptic women by immunohistochemistry. Clin Exp Obstet Gynecol 2007;34:228–31.Search in Google Scholar
16. ACOG Committee on Obstetric Practice. ACOG practice bulletin. Diagnosis and management of preeclampsia and eclampsia. Number 33, January 2002. American College of Obstetricians and Gynecologists. Int J Gynaecol Obstet 2002;77:67–75.10.1016/S0029-7844(01)01747-1Search in Google Scholar
17. Grill, S, Rusterholz, C, Zanetti-Dällenbach, R, Tercanli, S, Holzgreve, W, Hahn, S, et al.. Potential markers of preeclampsia--a review. Reprod Biol Endocrinol 2009;7:70. https://doi.org/10.1186/1477-7827-7-70.Search in Google Scholar PubMed PubMed Central
18. Veerbeek, JH, Post Uiterweer, ED, Nikkels, PG, Koenen, SV, van der Zalm, M, Koster, MPH, et al.. Biopsy techniques to study the human placental bed. Placenta 2015;36:775–82. https://doi.org/10.1016/j.placenta.2015.05.008.Search in Google Scholar PubMed
19. Livak, KJ, Schmittgen, TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C (T)) method. Methods 2001;25:402–8. https://doi.org/10.1006/meth.2001.1262.Search in Google Scholar PubMed
20. Sibai, BM, Stella, CL. Diagnosis and management of atypical preeclampsia-eclampsia. Am J Obstet Gynecol 2009;200:481. https://doi.org/10.1016/j.ajog.2008.07.048.Search in Google Scholar PubMed
21. Lyall, F. Priming and remodelling of human placental bed spiral arteries during pregnancy. Placenta 2005;26:S31–6. https://doi.org/10.1016/j.placenta.2005.02.010.Search in Google Scholar PubMed
22. Pinheiro, MB, Pinheiro, MB, Gomes, KB, Dusse, LMS. Fibrinolytic system in preeclampsia. Clin Chim Acta 2012;416:67–71. https://doi.org/10.1016/j.cca.2012.10.060.Search in Google Scholar PubMed
23. Duley, L. Pre-eclampsia and the hypertensive disorder of pregnancy. Br Med Bull 2003;416:161–76. https://doi.org/10.1093/bmb/ldg005.Search in Google Scholar PubMed
24. Lala, PK, Nandi, P. Mechanisms of trophoblast migration, endometrial angiogenesis in preeclampsia: the role of decorin. Cell Adhes Migrat 2016;10:111–25. https://doi.org/10.1080/19336918.2015.1106669.Search in Google Scholar PubMed PubMed Central
25. Van Beck, E, Peeters, LL. Pathogenesis of preeclampsia: a comprehensive model. Obstet Gynecol Surv 1998;53:233–9. https://doi.org/10.1097/00006254-199804000-00021.Search in Google Scholar
26. Baker, PN, Krasnow, J, Roberts, JM, Yeo, KT. Elevated serum levels of vascular endothelial growth factor in patients with preeclampsia. Obstet Gynecol 1995;86:815–21. https://doi.org/10.1016/0029-7844(95)00259-t.Search in Google Scholar
27. Kupferminc, MJ, Daniel, Y, Englender, T, Baram, A, Many, A, Ariel, J, et al.. Vascular endothelial growth factor is increased in patients with preeclampsia. Am J Reprod Immunol 1997;38:302–6. https://doi.org/10.1111/j.1600-0897.1997.tb00519.x.Search in Google Scholar
28. Eun, SL, Oh, MJ, Jae, WJ, Lim, JE, Seol, HJ, Lee, KJ, et al.. The levels of circulating vascular endothelial growth factor and soluble Flt-1 in pregnancies complicated by preeclampsia. J Kor Med Sci 2007;22:94–8.10.3346/jkms.2007.22.1.94Search in Google Scholar
29. Lyall, F, Young, A, Boswell, F, Kingdom, JC, Greer, IA. Placental expression of vascular endothelial growth factor in placentae from pregnancies complicated by pre-eclampsia and intrauterine growth restriction does not support placental hypoxia at delivery. Placenta 1997;18:269–76. https://doi.org/10.1016/s0143-4004(97)80061-6.Search in Google Scholar
30. Charnock-Jones, DS, Kaufmann, P, Mayhew, TM. Aspects of human fetoplacental vasculogenesis and angiogenesis. I. Molecular regulation. Placenta 2004;25:103–13. https://doi.org/10.1016/j.placenta.2003.10.004.Search in Google Scholar PubMed
31. Andraweera, PH, Dekker, GA, Roberts, CT. The vascular endothelial growth factor family in adverse pregnancy outcomes. Hum Reprod Update 2012;18:436–57. https://doi.org/10.1093/humupd/dms011.Search in Google Scholar PubMed
32. Tsatsaris, V, Goffin, F, Foidart, JM. Circulating angiogenic factors and preeclampsia. N Engl J Med 2004;350:2003–4. https://doi.org/10.1056/NEJM200405063501918.Search in Google Scholar PubMed
33. Cheung, CY. Vascular endothelial growth factor: possible role in fetal development and placental function. J Soc Gynecol Invest 1997;4:169–77. https://doi.org/10.1177/107155769700400401.Search in Google Scholar
34. Bates, DO, MacMillan, PP, Manjaly, JG, Qiu, Y, Hudson, SJ, Bevan, HS, et al.. The endogenous anti-angiogenic family of splice variants of VEGF, VEGFxxxb, are down-regulated in pre-eclamptic placentae at term. Clin Sci (Lond) 2006;110:575–85. https://doi.org/10.1042/CS20050292.Search in Google Scholar PubMed
35. Simpson, AJ, Booth, NA, Moore, NR, Lewis, SJ, Gray, RS. Circulating tissue-type plasminogen activator and plasminogen activator inhibitor type1 in proliferative diabetic retinopathy: a pilot study. Acta Diabetol 1999;36:155–8. https://doi.org/10.1007/s005920050159.Search in Google Scholar
36. Pepper, MS. Extracellular proteolysis and angiogenesis. Thromb Haemostasis 2001;86:346–55. https://doi.org/10.1055/s-0037-1616232.Search in Google Scholar
37. Cesarman, GM, Guevara, CA, Hajjar, KA. An endothelial cell receptor for plasminogen/tissue plasminogen activator (t-PA) II. Annexin II-mediated enhancement of t-PA dependent plasminogen activation. J Biol Chem 1994;269:21198–203. https://doi.org/10.1016/s0021-9258(17)31948-8.Search in Google Scholar
38. Ling, Q, Jacovina, AT, Deora, A, Febbraio, M, Simantov, R, Silverstein, RL. Annexin II regulates fibrin homeostasis and neoangiogenesis in vivo. J Clin Invest 2004;113:38–48. https://doi.org/10.1172/jci19684.Search in Google Scholar PubMed PubMed Central
39. Cesarman-Maus, G, Ríos-Luna, NP, Deora, AB, Huang, B, Villa, R, CraviotoMdel, C, et al.. Autoantibodies against the fibrinolytic receptor, annexin 2, in antiphospholipid syndrome. Blood 2006;107:4375–82. https://doi.org/10.1182/blood-2005-07-2636.Search in Google Scholar PubMed PubMed Central
40. Menell, JS, Cesarman, GM, Jacovina, AT, McLaughlin, MA, Lev, EA, Hajjar, KA. Annexin II and bleeding in acute promyelocyticleukemia. N Engl J Med 1999;340:994–1004. https://doi.org/10.1056/nejm199904013401303.Search in Google Scholar
41. Dassah, M, Deora, AB, He, K, Hajjar, KA. The endothelial cell annexin A2 system and vascular fibrinolysis. Gen Physiol Biophys 2009;28:F20–8.Search in Google Scholar
42. Gohil, R, Peck, G, Sharma, P. The genetics of venous thromboembolism. A meta-analysis involving approximately 120,000 cases and 180,000 controls. Thromb Haemostasis 2009;102:360–70. https://doi.org/10.1160/th09-01-0013.Search in Google Scholar PubMed
43. Sucak, GT, Acar, K, Sucak, A, Kirazli, S, Haznedar, R. Increased global fibrinolytic capacity as a clue for activated fibrinolysis in pre-eclampsia. Blood Coagul Fibrinolysis 2006;17:347–52. https://doi.org/10.1097/01.mbc.0000233364.72863.a0.Search in Google Scholar PubMed
44. Xin, H, Zhang, Y, Wang, H, Sun, S. Alterations of profibrinolytic receptor annexin A2 in pre-eclampsia: a possible role in placental thrombin formation. Thromb Res 2012;129:563–7. https://doi.org/10.1016/j.thromres.2011.07.039.Search in Google Scholar PubMed
© 2021 Walter de Gruyter GmbH, Berlin/Boston
Articles in the same Issue
- Frontmatter
- Minireview
- Can pulse wave velocity (PWV) alone express arterial stiffness? A neglected tool for vascular function assessment
- Review
- Hyponatremia in heart failure: not just 135 to 145
- Original Articles
- Effects of berberine on cholinesterases and monoamine oxidase activities, and antioxidant status in the brain of streptozotocin (STZ)-induced diabetic rats
- Paradoxical sleep deprivation induces oxidative stress in the submandibular glands of Wistar rats
- Terminalia arjuna supplementation ameliorates high fat diet-induced oxidative stress in nephrotoxic rats
- Decreased expression of annexin A2 and loss of its association with vascular endothelial growth factor leads to the deficient trophoblastic invasion in preeclampsia
- Algogen-induced vasosensory reflexes modulate short-term heart rate variability parameters in experimental rat models
- Assessment of sleep quality and its predictors among newly diagnosed psychiatric patients
- Ovalbumin/lipopolysaccharide induced vasculitis in rats: a new predictive model
- Dose-dependent and time-dependent metabolic, hemodynamic, and redox disturbances in dexamethasone-treated Wistar rats
- Effects of sleeve gastrectomy on neutrophil–lymphocyte ratio
- Effect of luteolin on the gene level expression of apoptosis-associated speck-like protein containing a caspase recruitment domain of NLRP3 inflammasome and NF-κB in rats subjected to experimental pancreatitis – influence of HSP70
- Effects of Onosma dichroanthum Boiss. root extract on AGS human gastric cancer cell-line
- Feasibility, face, and content validity of quantitative computed tomography in interstitial lung disease related to connective tissue diseases
- In vitro anticoagulant activity of selected medicinal plants: potential interactions with warfarin and development of new anticoagulants
- Normal reference value of orthodromic and antidromic sensory nerve conduction velocity of median nerve with intact palmaris longus tendon in apparently healthy individuals
- Short Communication
- Chemokine receptor antagonists with α1-adrenergic receptor blocker activity
Articles in the same Issue
- Frontmatter
- Minireview
- Can pulse wave velocity (PWV) alone express arterial stiffness? A neglected tool for vascular function assessment
- Review
- Hyponatremia in heart failure: not just 135 to 145
- Original Articles
- Effects of berberine on cholinesterases and monoamine oxidase activities, and antioxidant status in the brain of streptozotocin (STZ)-induced diabetic rats
- Paradoxical sleep deprivation induces oxidative stress in the submandibular glands of Wistar rats
- Terminalia arjuna supplementation ameliorates high fat diet-induced oxidative stress in nephrotoxic rats
- Decreased expression of annexin A2 and loss of its association with vascular endothelial growth factor leads to the deficient trophoblastic invasion in preeclampsia
- Algogen-induced vasosensory reflexes modulate short-term heart rate variability parameters in experimental rat models
- Assessment of sleep quality and its predictors among newly diagnosed psychiatric patients
- Ovalbumin/lipopolysaccharide induced vasculitis in rats: a new predictive model
- Dose-dependent and time-dependent metabolic, hemodynamic, and redox disturbances in dexamethasone-treated Wistar rats
- Effects of sleeve gastrectomy on neutrophil–lymphocyte ratio
- Effect of luteolin on the gene level expression of apoptosis-associated speck-like protein containing a caspase recruitment domain of NLRP3 inflammasome and NF-κB in rats subjected to experimental pancreatitis – influence of HSP70
- Effects of Onosma dichroanthum Boiss. root extract on AGS human gastric cancer cell-line
- Feasibility, face, and content validity of quantitative computed tomography in interstitial lung disease related to connective tissue diseases
- In vitro anticoagulant activity of selected medicinal plants: potential interactions with warfarin and development of new anticoagulants
- Normal reference value of orthodromic and antidromic sensory nerve conduction velocity of median nerve with intact palmaris longus tendon in apparently healthy individuals
- Short Communication
- Chemokine receptor antagonists with α1-adrenergic receptor blocker activity