ADM and SFLT-1 Expression in Placentas with Gestational Diabetes Mellitus

Öz

Aim: In this study, we aimed to examine the expression levels of Adrenomedullin (ADM) and soluble fms-like tyrosine kinase-1 (sFlt-1), two novel proteins found to be involved in vascular regulation in gestational diabetes mellitus (GDM), to compare the expression levels of these proteins in the histopathology of the disease and to observe the correlation of the expression intensity of these proteins with the disease. Methods: In our study, 20 healthy and 20 GDM placenta samples were obtained. Histologic follow-up was performed. 5µm thick sections were taken from these tissues and stained with Hematoxylin-Eosin and Periodic Acid Schiff (PAS). Immunohistochemically, ADM and sFlt-1 antibodies were studied. Results: In the GDM group, vascular dilatation and congestion in stem villus, hyperplasic endothelial cells, and increased syncytial bridges in the external part of the villi, mononuclear cell infiltration, pyknotic nuclei and cytoplasm loss in some of the decidual cells in the maternal region were observed. In the immunohistochemical examination, cytotrophoblast and syncytiotrophoblast cells of villous and syncytial nodes showed negative ADM expression. ADM was positively expressed in some cytotrophoblast cells of small villi, vascular endothelial cells and decidual cells. In the GDM group, sFlt-1 expression was positive in endothelial cells, some Hofbauer cells of mesenchymal connective tissue, decidual cell nuclei and membranes. Conclusion: ADM may be an important receptor in insulin metabolism to determine the glucose level because we found positive ADM expression in cytotrophoblasts and membranes of decidual cells. In addition, changes in endothelial cells of maternal and fetal regions and sFlt-1 expression in Hofbauer cells suggest that this molecule possibly plays a key role in the angiogenic effect.

Anahtar Kelimeler

• Placenta
• GDM
• PAS
• hematoxylin-eosin
• sFlt-1
• adrenomedullin

ADM AND SFLT-1 EXPRESSION IN PLACENTAS WITH GESTATIONAL DIABETES MELLITUS

Öz

Amaç: Bu çalışmada gestasyonel diyabetes mellitusta (GDM) vasküler regülasyonda rolü saptanan iki yeni protein olan Adrenomedullin (ADM) ve soluble fms-benzeri tirozin kinaz (sFlt-1)’in ekspresyon seviyelerini incelemeyi, hastalığın histopatolojisinde bu proteinlerin ekspresyon seviyelerini karşılaştırmayı ve bu proteinlerin ekspresyon yoğunluğunun hastalıkla korelasyonunu gözlemlemeyi amaçladık. Gereç ve Yöntem: Çalışmamızda 20 Normotansif ve 20 GDM’li plasenta örneği alındı. Histolojik takip yöntemiyle takip edildi. Bu dokulardan 5µm kalınlığında kesitler alınarak Hematoksilen-Eozin, Periodic Acid Schiff (PAS) boyamaları yapıldı. İmmunünohistokimyasal olarak ADM ve sFlt-1 antikorları çalışıldı. Bulgular: GDM grubunda; kök villuslarındaki kan damarlarında dilatasyon ve konjesyon, endotel hücrelerinde hiperplazi görüldü. Villusların dış kısmındaki sinsitiyal köprülerde artış, mononükleer hücre infiltrasyonu, maternal bölgedeki desidual hücrelerin bazılarında piknotik nükleuslar ve sitoplazma kaybı izlendi. İmmunohistokimyasal incelemede villusların sitotrofoblast ve sinsitiyotrofoblast hücrelerinde ve sinsitiyal düğümlerde negatif ADM ekspresyonu vardı. Küçük villusların bazı sitotrofoblast hücrelerinde, damar endotel hücrelerinde ve desidual hücrelerde pozitif ADM ekspresyonu görüldü. GDM grubunda sFlt-1 ekspresyonu endotel hücrelerinde, mezenşimal bağ doku içindeki bazı Hofbauer hücrelerinde, desidual hücre nükleuslarında ve membranlarında pozitif olarak gözlendi. Sonuç: Desidual hücre membranlarında, sitotrofoblastlarda ADM pozitif ekspresyon gösterdiğinden ADM’nin glikoz yoğunluğunun belirlenmesinde ve bununla ilişkili olarak insülin regülasyonunda önemli bir düzenleyici olabileceğini düşündürmüştür. Yine sFlt-1’in maternal ve fötal bölgelerdeki endotel hücresi üzerindeki etkileri ve Hofbauer hücrelerindeki ekspresyonu, anjiyogenik etkide bu molekülün anahtar rol alabileceği kanısını uyandırmıştır.

Anahtar Kelimeler

• placenta
• pas
• gdm
• ADM
• sFLT-1

Kaynakça

1. 1. Hod M, Kapur A, Sacks DA, et al. The International Federation of Gynecology and Obstetrics (FIGO) Initiative on gestational diabetes mellitus: A pragmatic guide for diagnosis, management, and care. Int J Gynaecol Obstet. 2015;131 Suppl 3:173-211. https://doi.org/10.1016/S0020-7292(15)30033-3
2. 2. Cvitic S, Desoye G, Hiden U. Glucose, insulin, and oxygen interplay in placental hypervascularisation in diabetes mellitus. Biomed Res Int. 2014;2014:145846. https://doi.org/10.1155/2014/145846
3. 3. Pardo F, Arroyo P, Salomón C, et al. Role of equilibrative adenosine transporters and adenosine receptors as modulators of the human placental endothelium in gestational diabetes mellitus. Placenta. 2013;34(12):1121-27. https://doi.org/10.1016/j.placenta.2013.09.007
4. 4. Wadsack C, Desoye G, Hiden U. The feto-placental endothelium in pregnancy pathologies. Wien Med Wochenschr. 2012;162(9-10):220-24. https://doi.org/10.1007/s10354-012-0075-2
5. 5. Gauster M, Desoye G, Tötsch M, et al. The placenta and gestational diabetes mellitus. Curr Diab Rep. 2012;12(1):16-23. https://doi.org/10.1007/s11892-011-0244-5
6. 6. Dong Y, Betancourt A, Belfort M, et al. Targeting Adrenomedullin to Improve Lipid Homeostasis in Diabetic Pregnancies. J Clin Endocrinol Metab. 2017;102(9):3425-36. https://doi.org/10.1210/jc.2017-00920
7. 7. Di Iorio R, Marinoni E, Urban G, et al. Fetomaternal adrenomedullin levels in diabetic pregnancy. Horm Metab Res. 2001;33(8):486-90. https://doi.org/10.1055/s-2001-16942
8. 8. Farina A, Eklund E, Bernabini D, et al. A First-Trimester Biomarker Panel for Predicting the Development of Gestational Diabetes. Reprod Sci. 2017;24(6):954-59. https://doi.org/10.1177/1933719116675057

9. 9. Romero R, Erez O, Hüttemann M, et al. Metformin, the aspirin of the 21st century: its role in gestational diabetes mellitus, prevention of preeclampsia and cancer, and the promotion of longevity. Am J Obstet Gynecol. 2017;217(3):282-302. https://doi.org/10.1016/j.ajog.2017.06.003
10. 10. Aktaş A, Aşır F, Başaran SO, et al. Granulocyte colony stimulating factor (GCSF) protected in ovarian tissues against ischemia-reperfusion injury. Journal of Drug Delivery and Therapeutics. 2022;12(4):26-30. https://doi.org/10.22270/jddt.v12i4.5538
11. 11. Calderon IM, Damasceno DC, Amorin RL, et al. Morphometric study of placental villi and vessels in women with mild hyperglycemia or gestational or overt diabetes. Diabetes research and clinical practice, (2007);78(1), 65-71. https://doi.org/10.1016/j.diabres.2007.01.023
12. 12. Metzger BE, Buchanan TA, Coustan DR, et al. Summary and recommendations of the Fifth International Workshop-Conference on Gestational Diabetes Mellitus. Diabetes Care. 2007;30 Suppl 2:251-60. https://doi.org/10.2337/dc07-s22513.
13. 13. Radaelli T, Varastehpour A, Catalano P, et al. Gestational diabetes induces placental genes for chronic stress and inflammatory pathways. Diabetes. 2003;52(12):2951-8. https://doi.org/10.2337/diabetes.52.12.2951
14. 14. Hauguel-de Mouzon S, Guerre-Millo M. The placenta cytokine network and inflammatory signals. Placenta. 2006;27(8):794-8. https://doi.org/10.1016/j.placenta.2005.08.009
15. 15. Jarmuzek P, Wielgos M, Bomba-Opon D. Placental pathologic changes in gestational diabetes mellitus. Neuro Endocrinol Lett. 2015;36(2):101-5.
16. 16. Sela S, Itin A, Natanson-Yaron S, et al. A novel human-specific soluble vascular endothelial growth factor receptor 1: cell type-specific splicing and implications to vascular endothelial growth factor homeostasis and preeclampsia. Circulation research. 2008;102(12):1566-74. https: /doi.org/1/ 0.1161/CIRCRESAHA.108.171504
17. 17. Desoye G. Hauguel-de mouzon S. The human placenta in gestational diabetes mellitus. Diabetes care. 2007;30:120-6. https://doi.org/10.2337/dc07-s203
18. 18. Asmussen I. Ultrastructure of the villi and fetal capillaries in placentas from smoking and nonsmoking mothers. BJOG: An International Journal of Obstetrics & Gynaecology. 1980;87(3):239-45. https://doi.org/10.1111/j.1471-0528.1980.tb04527.x
19. 19. Gheorman L, Pleşea I, Gheorman V. Histopathological considerations of placenta in pregnancy with diabetes. Rom J Morphol Embryol. 2012;53(2):329-36.
20. 20. Li N, Pan X, Zhang J, et al. Plasma levels of miR-137 and miR-124 are associated with Parkinson’s disease but not with Parkinson’s disease with depression. Neurological Sciences. 2017;38:761-7. https://doi.org/10.1007/s10072-017-2841-9
21. 21. Janota J, Pomyje J, Toth D, et al. Expression of angiopoietic factors in normal and type-I diabetes human placenta: a pilot study. European Journal of Obstetrics & Gynecology and Reproductive Biology. 2003;111(2):153-6. https://doi.org/10.1016/S0301-2115(03)00204-5
22. 22. Dong Y, Banadakoppa M, Chauhan M, et al. Circulating adrenomedullin is elevated in gestational diabetes and its role in impaired insulin production by β-cells. The Journal of Clinical Endocrinology and Metabolism. 2019;104(3):697-706. https://doi.org/10.1210/jc.2018-01119
23. 23. Maynard SE, Min JY, Merchan J, 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):649-658. https://doi.org/10.1172/JCI17189.
24. 24. Kanenishi K, Kuwabara H, Ueno M, et al. Immunohistochemical adrenomedullin expression is decreased in the placenta from pregnancies with pre‐eclampsia. Pathology international. 2000;50(7):536-40. https://doi.org/10.1046/j.1440-1827.2000.01085.x