PREEKLAMPSIYE BAĞLI PLASENTAL DEĞİŞİKLİKLERİN İMMUNOHİSTOKİMYASAL İNCELENMESİ

Abstract

Amaç: Preeklampsi, gebeliğin 20. haftasından sonra ortaya çıkan patogenezi hala tam anlaşılamamış hipertansiyon, proteinüri ile karakterize multisistemik bir sendromdur. Bu çalışmada, preeklampsi patogenezinde önemli rollere sahip olduğu düşünülen oksidatif stres mekanizmasının aydınlatılmasına yardımcı olabilmek için angiyogenezde majör rolü olan, endotel fonksiyon bozukluğu ve endotel fonksiyonunu koruyucu olduğu düşünülen VEGF-A (Vasküler endotelyal büyüme faktörü-A) ve oksidatif stresin birçok aşamasında farklı işlevleri olan HSP90 (ısı şoku proteini90) ile preeklamptik plasentalardaki değişiklikleri immünohistokimyasal olarak incelemeyi amaçladık. Gereç ve Yöntemler: Doku örnekleri vaka grubunda 10 preeklampsili gebeden ve kontrol grubunda ise 10 sağlıklı gebeden alındı. Gebelerin yaş, gravida ve parite gibi bilgileri veri olarak alındı. Kontrol grubu ve preeklampsili gebelerden alınan örnekler histokimyasal, immunohistokimyasal ve elektron mikroskobik yöntemlerle değerlendirildi. Bulgular: Değerlendirmeler sonucu, preeklampsili gebelerin plasenta dokularında serbest villus sayısında azalma, villuslardaki fetal kapiller sayısında azalma, fetomaternal bariyerlerin morfolojik yetersizliği, villus stromasında kolajen artması, sinsisyotrofoblast bazal membranında kalınlaşma gibi histolojik farklılıklar gözlenmiştir. Bununla birlikte preeklamptik gebelerde plasental VEGF-A immünreaktivitesinin kontrole göre azaldığı, HSP90’ın ise arttığı saptanmıştır. Sonuç: Bu sonuçlar, her iki endojen molekülün de preeklampsi patogenezinde oldukça önemli rollere sahip olduğunu göstermektedir.

Keywords

• Preeklampsi
• plasenta
• immunohistokimya
• VEGF-A
• HSP90

References

1. 1. American College of Obstetricians and Gynecologists. Hypertension in pregnancy. ACOG Technical Bulletin No.: 219. Washington, DC: The College; 1996. p. 1-8.
2. 2. Am. Coll. Obstet. Gynecol. Comm. Obstet. Pract. 2002. Diagnosis and management of preeclampsia and eclampsia. Obstet. Gynecol. 99: 159–67.
3. 3. Hogberg U. The World Health Report 2005: "make every mother and child count" - including Africans. Scand J Public Health, 2005. 33(6): p. 409–11.
4. 4. Young BC , Levine RJ, Karumanchi SA. Pathogenesis of Preeclampsia. Annu Rev Pathol. 2010; 5: 173–92.
5. 5. Kong TY, De Wolf F, Robertson WB, Brosens I. Inadequate maternal vascular response to placentation in pregnancies complicated by pre-eclampsia and by small for-gestational age infants. Br J Obstet Gynaecol 1986; 93: 1049–59.
6. 6. Pijnenborg R, Dixon G, Robertson WB, Brosens I. Trophoblastic invasion of human decidua from 8 to 18 weeks of pregnancy. Placenta 1980; 1: 3–19.
7. 7. Cunningham FG, Leveno KJ, Gilstrap LC, Hauth JC, Wenstrom KD., Williams Obstetrics 21th edition. 2001: McGRAW-HILL.
8. 8. Cross CE, et al. Oxygen radicals and human disease. Ann Intern Med, 1987. 107(4): p. 526–45.

9. 9. Csermely P, et al. The 90-kDa molecular chaperone family: structure, function, and clinical applications. A comprehensive review. Pharmacol Ther, 1998. 79(2): p. 129–68.
10. 10. Padmini E, Venkatraman U and Srinivasan L. Mechanism of JNK signal regulation by placental HSP70 and HSP90 in endothelial cell during preeclampsia. Toxicol Mech Methods, 2012. 22(5): p. 367–74.
11. 11. Simmons LA, et al. Uteroplacental blood flow and placental vascular endothelial growth factor in normotensive and pre-eclamptic pregnancy. BJOG, 2000. 107(5): p. 678–85.
12. 12. Akercan F, et al. The immunohistochemical evaluation of VEGF in placenta biopsies of pregnancies complicated by preeclampsia. Archives of Gynecology and Obstetrics, 2008. 277(2): p. 109–14.
13. 13. Zhou Y, 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(4): p. 1405–23.
14. 14. Cirpan T, et al. Evaluation of VEGF in placental bed biopsies from preeclamptic women by immunohistochemistry. Clin Exp Obstet Gynecol, 2007. 34(4): p. 228–31.
15. 15. Padmini E. Placental Heat Shock Protein 70 Overexpression Confers Resistance Against Oxidative Stress in Preeclampsia. Turk J Med Sci, 2008. 38 (1): p. 27–34.
16. 16. Sahin Z,et al. Distribution of Notch Family Proteins in Intrauterine Growth Restriction and Hypertension Complicated Human Term Placentas. Acta Histochem. 2011; 113(3): 270–6.
17. 17. Cooper JC, et al. VEGF mRNA levels in placentae from pregnancies complicated by pre-eclampsia. Br J Obstet Gynaecol, 1996. 103(12): p. 1191–6.
18. 18. Saeed I. Histomorphological Changes in Placentae of Pre-Eclamptic Mothers with Reference to Vasculosyncytial Membrane Thickness and Syncytial Knot Formation. Journal of Rawalpindi Medical College (JRMC), 2012. 16(1): p. 51–54.
19. 19. de Luca Brunori I, et al. Placental barrier breakage in preeclampsia: ultrastructural evidence. Eur J Obstet Gynecol Reprod Biol, 2005. 118(2): p. 182–9.
20. 20. Clark DE, et al. Localization of VEGF and expression of its receptors flt and KDR in human placenta throughout pregnancy. Human Reproduction, 1996. 11(5): p. 1090–8.
21. 21. Jackson MR, et al. Localization of two angiogenic growth factors (PDECGF and VEGF) in human placentae throughout gestation. Placenta, 1994. 15(4): p. 341–53.
22. 22. Schiessl B, et al. Localization of angiogenic growth factors and their receptors in the human placental bed throughout normal human pregnancy. Placenta, 2009. 30(1): p. 79–87.
23. 23. Vuorela P, et al. Expression of vascular endothelial growth factor and placenta growth factor in human placenta. Biology of Reproduction, 1997. 56(2): p. 489–94.
24. 24. Clark DE, et al. Comparison of expression patterns for placenta growth factor, vascular endothelial growth factor (VEGF), VEGF-B and VEGF-C in the human placenta throughout gestation. J Endocrinol, 1998. 159(3): p. 459–67.
25. 25. Torry DS, et al. Preeclampsia is associated with reduced serum levels of placenta growth factor. Am J Obstet Gynecol, 1998. 179(6 Pt 1): p. 1539–44.
26. 26. Reuvekamp A, et al. Selective deficit of angiogenic growth factors characterises pregnancies complicated by pre-eclampsia. Br J Obstet Gynaecol, 1999. 106(10): p. 1019–22.
27. 27. Zhang, EG, et al. The regulation and localization of angiopoietin-1, -2, and their receptor Tie2 in normal and pathologic human placentae. Molecular Medicine, 2001. 7(9): p. 624–35.
28. 28. Wulff C, et al. Angiogenesis during primate placentation in health and disease. Reproduction, 2003. 126(5): p. 569–77.
29. 29. Khong TY, et al. Inadequate maternal vascular response to placentation in pregnancies complicated by pre-eclampsia and by small-for-gestational age infants. Br J Obstet Gynaecol, 1986. 93(10): p. 1049–59.
30. 30. Zhou Y, Damsky CH and Fisher SJ. Preeclampsia is associated with failure of human cytotrophoblasts to mimic a vascular adhesion phenotype. One cause of defective endovascular invasion in this syndrome? J Clin Invest, 1997. 99(9): p. 2152–64.
31. 31. Zhou Y, et al. Preeclampsia is associated with abnormal expression of adhesion molecules by invasive cytotrophoblasts. J Clin Invest, 1993. 91(3): p. 950–60.
32. 32. Andraweera PH, Dekker GA and Roberts CT. The vascular endothelial growth factor family in adverse pregnancy outcomes. Hum Reprod Update, 2012. 18(4): p. 436–57.
33. 33. Lyall F, et al. 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(4): p. 269–76.
34. 34. Tsatsaris V, Goffin F, Munaut C, Brichant JF, Pignon MR, Noel A, Schaaps JP, Cabrol D, Frankenne F, Foidart JM (2003) Overexpression of the soluble vascular endothelial growth factor receptor in preeclamptic patients: pathophysiological consequences. Clin Endocrinol Metab 88(11): 5555–63.
35. 35. Chung JY, et al. Differential expression of vascular endothelial growth factor (VEGF), endocrine gland derived-VEGF, and VEGF receptors in human placentas from normal and preeclamptic pregnancies. J Clin Endocrinol Metab, 2004. 89(5): p. 2484–90.
36. 36. Ranheim T, Staff AC, and Henriksen T. VEGF mRNA is unaltered in decidual and placental tissues in preeclampsia at delivery. Acta Obstet Gynecol Scand, 2001. 80(2): p.93–8.
37. 37. Brosens IA, Robertson WB and Dixon HG. The role of the spiral arteries in the pathogenesis of preeclampsia. Obstet Gynecol Annu, 1972. 1: p. 177–91.
38. 38. Burton GJ et al., Rheological and physiological consequences of conversion of the maternal spiral arteries for uteroplacental blood flow during human pregnancy. Placenta, 2009. 30(6): p. 473–82.
39. 39. Maynard E, 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(5): p. 649–58.
40. 40. Polliotti BM et al. Second-trimester maternal serum placental growth factor and vascular endothelial growth factor for predicting severe, early-onset preeclampsia. Obstetrics and Gynecology, 2003. 101(6): p. 1266–74.
41. 41. Li Z et al. Recombinant vascular endothelial growth factor 121 attenuates hypertension and improves kidney damage in a rat model of preeclampsia. Hypertension, 2007. 50(4): p. 686–92.
42. 42. Livingston JC et al. Reductions of vascular endothelial growth factor and placental growth factor concentrations in severe preeclampsia. Am J Obstet Gynecol, 2000. 183(6): p. 1554–7.
43. 43. Levine RJ et al., Circulating angiogenic factors and the risk of preeclampsia. N Engl J Med, 2004. 350(7): p. 672–83.
44. 44. Koga K, Osuga Y, Yoshino O et al. Elevated serum soluble vascular endothelial growth factor receptor1 (sVEGFR-1) levels in women with preeclampsia. J. Clin. Endocrinol. Metab. 2003. 88, 2348–51.
45. 45. Lindquist S, Craig EA. The heat-shock proteins. Annu. Rev. Genet. 1988. 22: 631–77.
46. 46. Hartl FU, Martin J, Neupert W. Protein Folding in the Cell: The Role of Molecular Chaperones Hsp70 and Hsp60. Annu Rev Biophys Biomol Struct. 1992; 21: 293–322.
47. 47. Chappell LC et al. Effect of antioxidants on the occurrence of pre-eclampsia in women at increased risk: a randomised trial. Lancet, 1999. 354(9181): p. 810–6.
48. 48. Cooke CL and Davidge ST. Peroxynitrite increases iNOS through NF-kappaB and decreases prostacyclin synthase in endothelial cells. Am J Physiol Cell Physiol, 2002. 282(2): p. C395–402.
49. 49. Roggensack AM, Zhang Y and Davidge ST. Evidence for peroxynitrite formation in the vasculature of women with preeclampsia. Hypertension, 1999. 33(1): p. 83–9.
50. 50. Garcia-Cardena G, et al. Dynamic activation of endothelial nitric oxide synthase by Hsp90. Nature, 1998. 392(6678): p. 821–4.
51. 51. Gu Y, et al. Increased superoxide generation and decreased stress protein Hsp90 expression in human umbilical cord vein endothelial cells (HUVECs) from pregnancies complicated by preeclampsia. Hypertension in Pregnancy, 2006. 25(3): p. 169–82.