PREEKLAMPSİ PATOFİZYOLOJİSİNDE ROL OYNAYAN MOLEKÜLER YOLAKLAR

Yıl 2023, Cilt: 24 Sayı: 3, 380 - 387, 13.07.2023

Damla Gül Fındık , Gülnur Take

https://doi.org/10.18229/kocatepetip.988858

Öz

Preeklampsi (PE) gebeliklerin yaklaşık % 4-5’inde görülen, hipertansiyon ve üriner proteinüri ile seyreden obstetrik bir hastalıktır. Maternal ve fetal komplikasyonlara neden olabilmektedir. PE alanında çok sayıda yapılan araştırmalara rağmen altta yatan patogenez hala belirsizdir. Ancak ilgili bu araştırmalar ile birlikte PE’yi tetikleyen çok sayıda moleküler mekanizma olduğu sonucuna varılmıştır. Bu moleküler mekanizmalardan yola çıkarak PE iki evrede incelenebilir. İlk evre anormal plasentasyon nedeniyle oluşan plasental iskemidir. İkinci evrede ise iskemik plasentadan dolaşıma salınan nekrotik ve apoptotik faktörler, sistemik inflamasyon ve endotelyal disfonksiyona neden olur. Plasental hücrelerden salınan bu faktörlerden biri de antianjiyogenik faktörlerdir. Ayrıca PE’de antioksidan ve prooksidan mekanizmalarda rekürren iskemi reperfüzyon hasarından dolayı olduğu düşünülen dengesizlik mevcuttur. PE’deki sistemik inflamatuar yanıt maternal immün hücrelerin trofoblastlarla teması sonucu ortaya çıkan immün yanıtla ilişkilendirilmektedir. Bu derlemenin amacı PE'ye giden yolda rol oynayan mevcut moleküler mekanizmaları göstermektir. İlgili moleküler mekanizmaların daha iyi anlaşılması doğrutusunda gelişen PE patogenezine dair yeni görüşler, ilerideki çalışmalara ışık tutacaktır.

Anahtar Kelimeler

Preeklampsi, Anjiyogenik proteinler, İnflamasyon, Plasentasyon

MOLECULAR PATHWAYS THAT PLAY A ROLE IN THE PREECLAMPSIA PATHOPHYSIOLOGY

Öz

Preeclampsia (PE) is an obstetric disease seen in approximately 4-5% of pregnancies progressing with hypertension and urinary proteinuria. It may cause maternal and fetal complications. Despite numerous researches in the field of PE, the underlying pathogenesis remains unclear. However, with these related studies, it has been concluded that there are many molecular mechanisms that trigger PE. Based on these molecular mechanisms, PE can be examined in two stages. The first stage is placental ischemia caused by abnormal placentation. In the second stage, necrotic and apoptotic factors released from the ischemic placenta into the circulation cause systemic inflammation and endothelial dysfunction. One of these factors released from placental cells is the antiangiogenic factor. Also, there is an imbalance in the antioxidant and prooxidant mechanisms that are thought to be due to recurrent ischemia reperfusion injury in PE. The systemic inflammatory response in PE is associated with the immunological response resulting from the contact of the maternal immune cells with trophoblasts. The aim of this review is to present the current molecular mechanisms implicating the pathway leading to PE. The development of new insights into the pathogenesis of PE in conclusion of a better understanding of the relevant molecular mechanisms will guide further studies.

Anahtar Kelimeler

Preeclampsia, Angiogenic Proteins, Inflammation, Placentation

Kaynakça

• 1. Abalos E, Cuesta C, Grosso AL, et al. Global and regional estimates of preeclampsia and eclampsia: a systematic review. Eur J Obstet Gynecol Reprod Biol. 2013;170:1-7.
• 2. Armaly Z, Jadaon JE, Jabbour A, Abassi ZA. Preeclampsia: Novel Mechanisms and Potential Therapeutic Approaches. Front Physiol. 2018;9:973.
• 3. Ives CW, Sinkey R, Rajapreyar I, Tita ATN, Oparil S. Preeclampsia Pathophysiology and Clinical Presentations: JACC State-of-the-Art Review. Journal of the American College of Cardiology. 2020;76:1690-702.
• 4. Phipps EA, Thadhani R, Benzing T, Karumanchi SA. Pre-eclampsia: pathogenesis, novel diagnostics and therapies. Nature Reviews Nephrology. 2019:1.
• 5. Redman CW. Preeclampsia: a multi-stress disorder. Rev Med Interne. 2011;(32)1:41-4.
• 6. Lyall F. Priming and remodelling of human placental bed spiral arteries during pregnancy–a review. Placenta. 2005;26:31-6.
• 7. Fisher SJ. Why is placentation abnormal in preeclampsia? American journal of obstetrics and gynecology. 2015;213:115-22.
• 8. James JL, Whitley GS, Cartwright JE. Pre-eclampsia: fitting together the placental, immune and cardiovascular pieces. J Pathol. 2010;221:363-78.
• 9. Cindrova-Davies T, Van Patot MT, Gardner L, et al. Energy status and HIF signalling in chorionic villi show no evidence of hypoxic stress during human early placental development. MHR: Basic science of reproductive medicine. 2014;21:296-308.
• 10. Palmer K, Saglam B, Whitehead C, et al. Severe early-onset preeclampsia is not associated with a change in placental catechol O-methyltransferase (COMT) expression. The American journal of pathology. 2011;178:2484-8.
• 11. Burton GJ, Woods AW, Jauniaux E, et al. Rheological and physiological consequences of conversion of the maternal spiral arteries for uteroplacental blood flow during human pregnancy. Placenta. 2009;30:473- 82.
• 12. George EM, Cockrell K, Aranay M, Csongradi E, Stec DE, Granger JP. Induction of heme oxygenase 1 attenuates placental ischemia–induced hypertension. Hypertension. 2011;57:941-8.
• 13. Stavreus-Evers A, Masironi B, Landgren BM, Holmgren A, Eriksson H, Sahlin L. Immunohistochemical localization of glutaredoxin and thioredoxin in human endometrium: a possible association with pinopodes. Mol Hum Reprod. 2002;8:546-51.
• 14. Murdoch CE, Shuler M, Haeussler DJ et al. Glutaredoxin-1 up-regulation induces soluble vascular endothelial growth factor receptor 1, attenuating post-ischemia limb revascularization. J Biol Chem. 2014;289:8633-44.
• 15.Shibata E, Ejima K, Nanri H et al. Enhanced protein levels of protein thiol/disulphide oxidoreductases in placentae from pre-eclamptic subjects. Placenta. 2001;22:566-72.
• 16. Vaughan JE, Walsh SW. Activation of NF-kappaB in placentas of women with preeclampsia. Hypertens Pregnancy. 2012;31:243-51.
• 17. Geldenhuys J, Rossouw TM, Lombaard HA, Ehlers MM, Kock MM. Disruption in the Regulation of Immune Responses in the Placental Subtype of Preeclampsia. Front Immunol. 2018;9:1659.
• 18. Jabrane-Ferrat N, Siewiera J. The up side of decidual natural killer cells: new developments in immunology of pregnancy. Immunology. 2014;141:490-7.
• 19. Djurisic S, Hviid TV. HLA Class Ib Molecules and Immune Cells in Pregnancy and Preeclampsia. Front Immunol. 2014;5:652.
• 20. Goldman-Wohl D, Yagel S. NK cells and pre-eclampsia. Reprod Biomed Online. 2008;16:227-31.
• 21. Amodio G, Sales de Albuquerque R, Gregori S. New insights into HLA-G mediated tolerance. Tissue Antigens. 2014;84:255-63.
• 22. Wheeler KC, Jena MK, Pradhan BS et al. VEGF may contribute to macrophage recruitment and M2 polarization in the decidua. PloS one. 2018;13:e0191040.
• 23. Bellos I, Karageorgiou V, Kapnias D, Karamanli KE, Siristatidis C. The role of interleukins in preeclampsia: A comprehensive review. Am J Reprod Immunol. 2018;80:13055.
• 24. Chen H, Zhou X, Han TL, Baker PN, Qi H, Zhang H. Decreased IL-33 Production Contributes to Trophoblast Cell Dysfunction in Pregnancies with Preeclampsia. Mediators Inflamm. 2018;2018:9787239.
• 25. Lamarca B. The role of immune activation in contributing to vascular dysfunction and the pathophysiology of hypertension during preeclampsia. Minerva Ginecol. 2010;62:105-20.
• 26. Piccinni MP, Lombardelli L, Logiodice F, Kullolli O, Parronchi P, Romagnani S. How pregnancy can affect autoimmune diseases progression? Clin Mol Allergy. 2016;14:11.
• 27. Darmochwal-Kolarz D, Kludka-Sternik M, Tabarkiewicz J, et al. The predominance of Th17 lymphocytes and decreased number and function of Treg cells in preeclampsia. J Reprod Immunol. 2012;93:75-81.
• 28. Rahimzadeh M, Norouzian M, Arabpour F, Naderi N. Regulatory T-cells and preeclampsia: an overview of literature. Expert Rev Clin Immunol. 2016;12:209-27.
• 29. Redman CW, Sargent IL. Immunology of pre-eclampsia. Am J Reprod Immunol. 2010;63:534-43.
• 30. Alvarez F, Fritz JH, Piccirillo CA. Pleiotropic Effects of IL-33 on CD4(+) T Cell Differentiation and Effector Functions. Front Immunol. 2019;10:522.
• 31. Sones JL, Merriam AA, Seffens A, et al. Angiogenic factor imbalance precedes complement deposition in placentae of the BPH/5 model of preeclampsia. FASEB J. 2018;32:2574-86.
• 32. Tong M, Cheng S-b, Chen Q, et al. Aggregated transthyretin is specifically packaged into placental nano-vesicles in preeclampsia. Scientific reports. 2017;7:6694.
• 33. Sani HM, Vahed SZ, Ardalan M. Preeclampsia: A close look at renal dysfunction. Biomedicine & Pharmacotherapy. 2019;109:408-16.
• 34. Pandey AK, Singhi EK, Arroyo JP et al. Mechanisms of VEGF (Vascular Endothelial Growth Factor) inhibitor–associated hypertension and vascular disease. Hypertension. 2018;71:1-8.
• 35. Powe CE, Levine RJ, Karumanchi SA. Preeclampsia, a disease of the maternal endothelium: the role of antiangiogenic factors and implications for later cardiovascular disease. Circulation. 2011;123:2856-69.
• 36. Staff AC, Benton SJ, von Dadelszen P, et al. Redefining preeclampsia using placenta-derived biomarkers. Hypertension. 2013;61:932-42.
• 37. Gregory AL, Xu G, Sotov V, Letarte M. Review: the enigmatic role of endoglin in the placenta. Placenta. 2014;35:93-9.
• 38. Cudmore M, Ahmad S, Al-Ani B, et al. Negative regulation of soluble Flt-1 and soluble endoglin release by heme oxygenase-1. Circulation. 2007;115:1789-97.
• 39. Ahmed A. New insights into the etiology of preeclampsia: identification of key elusive factors for the vascular complications. Thrombosis research. 2011;127:72-5.
• 40. Quitterer U, Fu X, Pohl A, Bayoumy KM, Langer A, AbdAlla S. Beta-Arrestin1 Prevents Preeclampsia by Downregulation of Mechanosensitive AT1-B2 Receptor Heteromers. Cell. 2019;176:318-33 e19.