Modulation of Placental Angiogenesis by Metformin in a Rat Model of Gestational Diabetes

Overview

Journal Histochem Cell Biol

Publisher Springer

Date 2025 Jan 27

PMID 39869176

Authors

Basmah M Eldakhakhny

Fatma M Ghoneim

Mona F M Soliman

Salwa M Abo El-Khair

Ayman Z Elsamanoudy

Yousef M Almoghrabi

Passant M Mohie

Fatma E Hassan

Amany A Abd Elfattah

Affiliations

Soon will be listed here.

Abstract

Gestational diabetes mellitus (GDM) significantly disrupts placental structure and function, leading to complications such as intrauterine growth restriction (IUGR) and preeclampsia. This study aimed to investigate the effects of GDM on placental histology, angiogenesis, and oxidative stress, as well as evaluate metformin's protective role in mitigating these changes. A total of 60 pregnant Sprague-Dawley rats were divided into four groups: control, metformin-treated, GDM, and GDM with metformin. GDM was induced using streptozotocin (STZ) at 40 mg/kg, and metformin was administered at 200 mg/kg from gestational day (GD) 4 to GD17. Blood glucose and insulin levels were assessed, and Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) was calculated. Placentae were weighed and subjected to histological, immunohistochemical, and molecular analyses, focusing on key angiogenesis markers (VEGF, VEGFR, CD31, KLF2) and oxidative stress indicators (MDA, eNOS). GDM increased placental weight, angiogenesis (elevated VEGF, VEGFR, CD31), and oxidative stress (elevated MDA, eNOS). Histopathological changes included villous edema, membrane rupture, and hemosiderin deposition. Metformin treatment reduced placental weight; normalized VEGF, KLF2, and PlGF expression; and improved placental architecture. Additionally, oxidative stress was significantly reduced in metformin-treated GDM rats. In conclusion, GDM induces placental abnormalities, promoting excessive angiogenesis and oxidative stress, potentially leading to IUGR and other complications. Metformin showed protective effects by reducing placental overgrowth and restoring vascular and oxidative balance. These findings suggest that metformin may play a therapeutic role in improving placental health in GDM pregnancies, warranting further investigation into its long-term effects on fetal development and maternal health.

References

Abdelzaher W, Bahaa H, Elkhateeb R, Atta M, Fawzy M, Ahmed A . Role of JNK, ERK, and p38 MAPK signaling pathway in protective effect of sildenafil in cyclophosphamide-induced placental injury in rats. Life Sci. 2022; 293:120354. DOI: 10.1016/j.lfs.2022.120354. View

Aldahmash W, Alwasel S, Aljerian K . Gestational diabetes mellitus induces placental vasculopathies. Environ Sci Pollut Res Int. 2021; 29(13):19860-19868. DOI: 10.1007/s11356-021-17267-y. View

Al-Ofi E, Alrafiah A, Maidi S, Almaghrabi S, Hakami N . Altered Expression of Angiogenic Biomarkers in Pregnancy Associated with Gestational Diabetes. Int J Gen Med. 2021; 14:3367-3375. PMC: 8286247. DOI: 10.2147/IJGM.S316670. View

Arshad R, Kanpurwala M, Karim N, Hassan J . Effects of Diet and Metformin on placental morphology in Gestational Diabetes Mellitus. Pak J Med Sci. 2017; 32(6):1522-1527. PMC: 5216313. DOI: 10.12669/pjms.326.10872. View

Barrow H, Guo X, Wandall H, Pedersen J, Fu B, Zhao Q . Serum galectin-2, -4, and -8 are greatly increased in colon and breast cancer patients and promote cancer cell adhesion to blood vascular endothelium. Clin Cancer Res. 2011; 17(22):7035-46. DOI: 10.1158/1078-0432.CCR-11-1462. View

Barta P, Kamaraj R, Kucharova M, Novy Z, Petrik M, Bendova K . Preparation, Affinity, and Biodistribution of Receptor-Specific Ga-Labeled Peptides Targeting Vascular Endothelial Growth Factor Receptors. Bioconjug Chem. 2022; 33(10):1825-1836. DOI: 10.1021/acs.bioconjchem.2c00272. View

Bellos I, Karageorgiou V, Kapnias D, Karamanli K, Siristatidis C . The role of interleukins in preeclampsia: A comprehensive review. Am J Reprod Immunol. 2018; 80(6):e13055. DOI: 10.1111/aji.13055. View

Bhattacharya R, SenBanerjee S, Lin Z, Mir S, Hamik A, Wang P . Inhibition of vascular permeability factor/vascular endothelial growth factor-mediated angiogenesis by the Kruppel-like factor KLF2. J Biol Chem. 2005; 280(32):28848-51. DOI: 10.1074/jbc.C500200200. View

Bianco M, Josefson J . Hyperglycemia During Pregnancy and Long-Term Offspring Outcomes. Curr Diab Rep. 2019; 19(12):143. PMC: 7008468. DOI: 10.1007/s11892-019-1267-6. View

10.

Blois S, Ilarregui J, Tometten M, Garcia M, Orsal A, Cordo-Russo R . A pivotal role for galectin-1 in fetomaternal tolerance. Nat Med. 2007; 13(12):1450-7. DOI: 10.1038/nm1680. View

11.

Cemek M, Kaga S, Simsek N, Buyukokuroglu M, Konuk M . Antihyperglycemic and antioxidative potential of Matricaria chamomilla L. in streptozotocin-induced diabetic rats. J Nat Med. 2008; 62(3):284-93. DOI: 10.1007/s11418-008-0228-1. View

12.

Charalambous C, Drakou K, Nicolaou S, Georgiades P . Novel spatiotemporal glycome changes in the murine placenta during placentation based on BS-I lectin binding patterns. Anat Rec (Hoboken). 2013; 296(6):921-32. DOI: 10.1002/ar.22698. View

13.

Chen D, Zheng J . Regulation of placental angiogenesis. Microcirculation. 2013; 21(1):15-25. PMC: 5589442. DOI: 10.1111/micc.12093. View

14.

Colomb F, Wang W, Simpson D, Zafar M, Beynon R, Rhodes J . Galectin-3 interacts with the cell-surface glycoprotein CD146 (MCAM, MUC18) and induces secretion of metastasis-promoting cytokines from vascular endothelial cells. J Biol Chem. 2017; 292(20):8381-8389. PMC: 5437243. DOI: 10.1074/jbc.M117.783431. View

15.

Correa I, Ruano R, Takiuti N, Francisco R, Bevilacqua E, Zugaib M . Expression of angiogenic factors in placenta of stressed rats. Reprod Fertil Dev. 2012; 24(6):851-8. DOI: 10.1071/RD11202. View

16.

Croci D, Cerliani J, DAlotto-Moreno T, Mendez-Huergo S, Mascanfroni I, Dergan-Dylon S . Glycosylation-dependent lectin-receptor interactions preserve angiogenesis in anti-VEGF refractory tumors. Cell. 2014; 156(4):744-58. DOI: 10.1016/j.cell.2014.01.043. View

17.

Cvitic S, Desoye G, Hiden U . Glucose, insulin, and oxygen interplay in placental hypervascularisation in diabetes mellitus. Biomed Res Int. 2014; 2014:145846. PMC: 4167234. DOI: 10.1155/2014/145846. View

18.

Dallaglio K, Bruno A, Cantelmo A, Esposito A, Ruggiero L, Orecchioni S . Paradoxic effects of metformin on endothelial cells and angiogenesis. Carcinogenesis. 2014; 35(5):1055-66. PMC: 4004203. DOI: 10.1093/carcin/bgu001. View

19.

DeCensi A, Puntoni M, Gandini S, Guerrieri-Gonzaga A, Johansson H, Cazzaniga M . Differential effects of metformin on breast cancer proliferation according to markers of insulin resistance and tumor subtype in a randomized presurgical trial. Breast Cancer Res Treat. 2014; 148(1):81-90. PMC: 4196136. DOI: 10.1007/s10549-014-3141-1. View

20.

Dewerchin M, Carmeliet P . PlGF: a multitasking cytokine with disease-restricted activity. Cold Spring Harb Perspect Med. 2012; 2(8). PMC: 3405829. DOI: 10.1101/cshperspect.a011056. View