{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T12:00:57Z","timestamp":1787313657336,"version":"build-2736575974"},"reference-count":34,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2025,10,30]],"date-time":"2025-10-30T00:00:00Z","timestamp":1761782400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Research, Development and Innovation Office, Hungary","award":["NKFI-FK19-132499"],"award-info":[{"award-number":["NKFI-FK19-132499"]}]},{"name":"\u201cGeza Hetenyi\u201d Grant, University of Szeged","award":["5S 724 (A202)"],"award-info":[{"award-number":["5S 724 (A202)"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Life"],"abstract":"<jats:p>Background: Obesity and gestational diabetes mellitus (GDM) are the most common metabolic conditions that have an unfavorable impact on maternal and fetal health. Maternal obesity and GDM are often associated with placental dysfunction and structural alterations. The apelin receptor (APLNR), vascular endothelial growth factor (VEGF), leptin, and DNA methylation play crucial roles in placental function. We aimed to investigate the placental volume and vascularization, and to determine the changes in these markers in obese and GDM mothers. Material and Methods: In our study, we investigated the human placenta (n = 48) at term. The placental structural analyses on volume and vascularization were conducted using three-dimensional ultrasound before labor. Placental APLNR expression was determined using RT-PCR, and leptin and VEGF concentrations using ELISA in placental tissues. Global DNA methylation was measured using colometric assay. Results: The age of GDM mothers was significantly higher than that of normal and obese mothers. The gestation length of GDM mothers was significantly shorter than that of normal and obese mothers. The placental volume was significantly higher in obese and GDM cases compared with normal cases. Vascularization indices (VI, FI, VFI) were significantly depressed in GDM and obesity. In the case of biomarker studies, APLNR, leptin, and VEGF showed similar decreases in obese and GDM placentas. Based on our results, the effect of GDM, not obesity, was more pronounced for these biomarkers. VEGF reduction correlates with three-dimensional placental vascularity studies. The DNA methylation was significantly elevated in both GDM and obese placental samples, while the GDM effect was more pronounced. Conclusions: This study is the first to demonstrate structural alterations of the placenta using placental tissue biomarkers in obesity and gestational diabetes mellitus (GDM). We found that both GDM and obesity affect placental volume and vascularity, as indicated by reduced leptin and VEGF levels, presumably mediated by epigenetic effects. Our findings may provide a novel therapeutic target for improving abnormal placental function caused by GDM and obesity.<\/jats:p>","DOI":"10.3390\/life15111691","type":"journal-article","created":{"date-parts":[[2025,10,31]],"date-time":"2025-10-31T02:48:28Z","timestamp":1761878908000},"page":"1691","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Placental Volume, Vascularization, and Epigenetic Modifications in Obesity and Gestational Diabetes: A 3-D Ultrasound and Molecular Analysis"],"prefix":"10.3390","volume":"15","author":[{"given":"Balint","family":"Kolcsar","sequence":"first","affiliation":[{"name":"Department of Obstetrics and Gynecology, Albert Szent-Gy\u00f6rgyi Medical School, University of Szeged, H-6725 Szeged, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2746-5372","authenticated-orcid":false,"given":"Kata Kira","family":"Kemeny","sequence":"additional","affiliation":[{"name":"Department of Pharmacodynamics and Biopharmacy, Faculty of Pharmacy, University of Szeged, H-6720 Szeged, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7485-9895","authenticated-orcid":false,"given":"Zoltan","family":"Kozinszky","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Albert Szent-Gy\u00f6rgyi Medical School, University of Szeged, H-6725 Szeged, Hungary"},{"name":"Capio Specialized Center for Gynecology, Solna, 171 45, Stockholm, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5219-8491","authenticated-orcid":false,"given":"Eszter","family":"Ducza","sequence":"additional","affiliation":[{"name":"Department of Pharmacodynamics and Biopharmacy, Faculty of Pharmacy, University of Szeged, H-6720 Szeged, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1168-7261","authenticated-orcid":false,"given":"Andrea","family":"Suranyi","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Albert Szent-Gy\u00f6rgyi Medical School, University of Szeged, H-6725 Szeged, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,10,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"D\u0142uski, D.F., Rusza\u0142a, M., Rudzi\u0144ski, G., Po\u017carowska, K., Brzuszkiewicz, K., and Leszczy\u0144ska-Gorzelak, B. (2022). Evolution of Gestational Diabetes Mellitus across Continents in 21st Century. IJERPH, 19.","DOI":"10.3390\/ijerph192315804"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1097\/OGX.0000000000000899","article-title":"Diagnosis and Management of Gestational Diabetes Mellitus: An Overview of National and International Guidelines","volume":"76","author":"Tsakiridis","year":"2021","journal-title":"Obstet. Gynecol. Surv."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"110874","DOI":"10.1016\/j.diabres.2023.110874","article-title":"Pregnancy Outcomes of Women with Untreated \u2018Mild\u2019 Gestational Diabetes (Gestational Diabetes by the WHO 2013 but Not by the WHO-1999 Diagnostic Criteria)\u2014A Population-Based Cohort Study","volume":"203","author":"Visolyi","year":"2023","journal-title":"Diabetes Res. Clin. Pract."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1396","DOI":"10.1007\/s00125-016-3985-5","article-title":"Gestational Diabetes Mellitus and Long-Term Consequences for Mother and Offspring: A View from Denmark","volume":"59","author":"Damm","year":"2016","journal-title":"Diabetologia"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"109050","DOI":"10.1016\/j.diabres.2021.109050","article-title":"IDF Diabetes Atlas: Estimation of Global and Regional Gestational Diabetes Mellitus Prevalence for 2021 by International Association of Diabetes in Pregnancy Study Group\u2019s Criteria","volume":"183","author":"Wang","year":"2022","journal-title":"Diabetes Res. Clin. Pract."},{"key":"ref_6","unstructured":"WHO Report: Obesity and Overweight 2024. Available online: https:\/\/Www.Who.Int\/News-Room\/Fact-Sheets\/Detail\/Obesity-and-Overweight."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"118310","DOI":"10.1016\/j.lfs.2020.118310","article-title":"Apelin\/Apelin Receptor: A New Therapeutic Target in Polycystic Ovary Syndrome","volume":"260","author":"Liu","year":"2020","journal-title":"Life Sci."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Hu, S., Wang, D., Liu, W., Wang, Y., Chen, J., and Cai, X. (2024). Apelin Receptor Dimer: Classification, Future Prospects, and Pathophysiological Perspectives. Biochim. Et Biophys. Acta (BBA)-Mol. Basis Dis., 1870.","DOI":"10.1016\/j.bbadis.2024.167257"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1006\/bbrc.1998.9489","article-title":"Isolation and Characterization of a Novel Endogenous Peptide Ligand for the Human APJ Receptor","volume":"251","author":"Tatemoto","year":"1998","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1016\/j.cca.2018.05.012","article-title":"Review: Apelin in Disease","volume":"483","author":"Antushevich","year":"2018","journal-title":"Clin. Chim. Acta"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"842","DOI":"10.1631\/jzus.B1600009","article-title":"Overweight and Obesity versus Concentrations of VEGF-A, SVEGFR-1, and SVEGFR-2 in Plasma of Patients with Lower Limb Chronic Ischemia","volume":"17","author":"Gadomska","year":"2016","journal-title":"J. Zhejiang Univ. Sci. B"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Ballmer-Hofer, K. (2018). Vascular Endothelial Growth Factor, from Basic Research to Clinical Applications. IJMS, 19.","DOI":"10.3390\/ijms19123750"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"400","DOI":"10.1186\/s12967-022-03603-4","article-title":"Vascular Endothelial Growth Factor and Its Receptors Regulation in Gestational Diabetes Mellitus and Eclampsia","volume":"20","author":"Bolatai","year":"2022","journal-title":"J. Transl. Med."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Obradovic, M., Sudar-Milovanovic, E., Soskic, S., Essack, M., Arya, S., Stewart, A.J., Gojobori, T., and Isenovic, E.R. (2021). Leptin and Obesity: Role and Clinical Implication. Front. Endocrinol., 12.","DOI":"10.3389\/fendo.2021.585887"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Guadix, P., Corrales, I., Vilari\u00f1o-Garc\u00eda, T., Rodr\u00edguez-Chac\u00f3n, C., S\u00e1nchez-Jim\u00e9nez, F., Jim\u00e9nez-Cortegana, C., Due\u00f1as, J.L., S\u00e1nchez-Margalet, V., and P\u00e9rez-P\u00e9rez, A. (2023). Expression of Nutrient Transporters in Placentas Affected by Gestational Diabetes: Role of Leptin. Front. Endocrinol., 14.","DOI":"10.3389\/fendo.2023.1172831"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"390","DOI":"10.1111\/joim.13496","article-title":"The Potential of DNA Methylation as a Biomarker for Obesity and Smoking","volume":"292","author":"Heikkinen","year":"2022","journal-title":"J. Intern. Med."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"371","DOI":"10.1038\/s41576-018-0004-3","article-title":"DNA Methylation-Based Biomarkers and the Epigenetic Clock Theory of Ageing","volume":"19","author":"Horvath","year":"2018","journal-title":"Nat. Rev. Genet."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"717","DOI":"10.1042\/EBC20190031","article-title":"DNA Methylation at the Crossroads of Gene and Environment Interactions","volume":"63","author":"Law","year":"2019","journal-title":"Essays Biochem."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1038\/npp.2012.112","article-title":"DNA Methylation and Its Basic Function","volume":"38","author":"Moore","year":"2013","journal-title":"Neuropsychopharmacology"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"156","DOI":"10.1006\/abio.1987.9999","article-title":"Single-Step Method of RNA Isolation by Acid Guanidinium Thiocyanate\u2013Phenol\u2013Chloroform Extraction","volume":"162","author":"Chomzynski","year":"1987","journal-title":"Anal. Biochem."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"e37329","DOI":"10.1016\/j.heliyon.2024.e37329","article-title":"Cooperation of Aquaporin 5 and the Adrenergic System in the Initiation of Birth in Rat Model","volume":"10","author":"Barna","year":"2024","journal-title":"Heliyon"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1007\/s11892-014-0489-x","article-title":"Long-Term Health Outcomes in Offspring Born to Women with Diabetes in Pregnancy","volume":"14","author":"Fraser","year":"2014","journal-title":"Curr. Diabetes Rep."},{"key":"ref_23","first-page":"1","article-title":"Trends and Characteristics in Gestational Diabetes: United States, 2016\u20132020","volume":"71","author":"Gregory","year":"2022","journal-title":"Natl. Vital Stat. Rep."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1016\/j.placenta.2024.05.138","article-title":"Kisspeptin Signalling and Its Correlation with Placental Ultrastructure and Clinical Outcomes in Pregnant South African Women with Obesity and Gestational Diabetes","volume":"154","author":"Musa","year":"2024","journal-title":"Placenta"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1229","DOI":"10.3109\/14767058.2015.1040985","article-title":"Placental Volume Relative to Fetal Weight Estimated by Sonography in Diabetic Pregnancies","volume":"29","author":"Kozinszky","year":"2016","journal-title":"J. Matern.-Fetal Neonatal Med."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1287","DOI":"10.1113\/JP284139","article-title":"Obesity and Gestational Diabetes Independently and Collectively Induce Specific Effects on Placental Structure, Inflammation and Endocrine Function in a Cohort of South African Women","volume":"601","author":"Musa","year":"2023","journal-title":"J. Physiol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"709","DOI":"10.1016\/j.placenta.2015.04.006","article-title":"Inflammation in Maternal Obesity and Gestational Diabetes Mellitus","volume":"36","author":"Pantham","year":"2015","journal-title":"Placenta"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1515\/ijamh-2021-0058","article-title":"Correlation between Obesity, Gestational Diabetes Mellitus, and Pregnancy Outcomes: An Overview","volume":"33","author":"Zehravi","year":"2021","journal-title":"Int. J. Adolesc. Med. Health"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1568","DOI":"10.1038\/s41366-024-01584-6","article-title":"Characterization of Obesity-Related Diseases and Inflammation Using Single Cell Immunophenotyping in Two Different Diet-Induced Obesity Models","volume":"48","author":"Ruppert","year":"2024","journal-title":"Int. J. Obes."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1146\/annurev-immunol-031210-101322","article-title":"Inflammatory Mechanisms in Obesity","volume":"29","author":"Gregor","year":"2011","journal-title":"Annu. Rev. Immunol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"903","DOI":"10.1016\/S0002-9378(99)70662-9","article-title":"Longitudinal Changes in Glucose Metabolism during Pregnancy in Obese Women with Normal Glucose Tolerance and Gestational Diabetes Mellitus","volume":"180","author":"Catalano","year":"1999","journal-title":"Am. J. Obstet. Gynecol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1111\/j.1749-6632.2010.05938.x","article-title":"Inflammation and Pregnancy: The Role of the Immune System at the Implantation Site","volume":"1221","author":"Mor","year":"2011","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Xu, P., Dong, S., Wu, L., Bai, Y., Bi, X., Li, Y., and Shu, C. (2022). Maternal and Placental DNA Methylation Changes Associated with the Pathogenesis of Gestational Diabetes Mellitus. Nutrients, 15.","DOI":"10.3390\/nu15010070"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"e13575","DOI":"10.1111\/obr.13575","article-title":"Leptin\u2013VEGF Crosstalk in Excess Body Mass and Related Disorders: A Systematic Review","volume":"24","author":"Skrypnik","year":"2023","journal-title":"Obes. Rev."}],"container-title":["Life"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2075-1729\/15\/11\/1691\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,31]],"date-time":"2025-10-31T03:13:23Z","timestamp":1761880403000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2075-1729\/15\/11\/1691"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,10,30]]},"references-count":34,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2025,11]]}},"alternative-id":["life15111691"],"URL":"https:\/\/doi.org\/10.3390\/life15111691","relation":{},"ISSN":["2075-1729"],"issn-type":[{"value":"2075-1729","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,10,30]]}}}