{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T01:08:27Z","timestamp":1787620107432,"version":"build-2736575974"},"reference-count":49,"publisher":"MDPI AG","issue":"22","license":[{"start":{"date-parts":[[2023,11,8]],"date-time":"2023-11-08T00:00:00Z","timestamp":1699401600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Korean government (MSIT)","award":["NRF 2017R1C1B5076378"],"award-info":[{"award-number":["NRF 2017R1C1B5076378"]}]},{"name":"Korean government (MSIT)","award":["NRF-2019R1I1A1A01059738"],"award-info":[{"award-number":["NRF-2019R1I1A1A01059738"]}]},{"name":"Korean government (MSIT)","award":["NRF-2021R1A2C2014591"],"award-info":[{"award-number":["NRF-2021R1A2C2014591"]}]},{"name":"Korean government (MSIT)","award":["NRF-2022R1I1A1A01064011"],"award-info":[{"award-number":["NRF-2022R1I1A1A01064011"]}]},{"name":"Korean government (MSIT)","award":["6-2017-0062"],"award-info":[{"award-number":["6-2017-0062"]}]},{"name":"Yonsei University College of Medicine","award":["NRF 2017R1C1B5076378"],"award-info":[{"award-number":["NRF 2017R1C1B5076378"]}]},{"name":"Yonsei University College of Medicine","award":["NRF-2019R1I1A1A01059738"],"award-info":[{"award-number":["NRF-2019R1I1A1A01059738"]}]},{"name":"Yonsei University College of Medicine","award":["NRF-2021R1A2C2014591"],"award-info":[{"award-number":["NRF-2021R1A2C2014591"]}]},{"name":"Yonsei University College of Medicine","award":["NRF-2022R1I1A1A01064011"],"award-info":[{"award-number":["NRF-2022R1I1A1A01064011"]}]},{"name":"Yonsei University College of Medicine","award":["6-2017-0062"],"award-info":[{"award-number":["6-2017-0062"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Maternal hyperglycemia, induced by gestational diabetes mellitus (GDM), has detrimental effects on fetal vascular development, ultimately increasing the risk of cardiovascular diseases in offspring. The potential underlying mechanisms through which these complications occur are due to functional impairment and epigenetic changes in fetal endothelial progenitor cells (EPCs), which remain less defined. We confirm that intrauterine hyperglycemia leads to the impaired angiogenic function of fetal EPCs, as observed through functional assays of outgrowth endothelial cells (OECs) derived from fetal EPCs of GDM pregnancies (GDM-EPCs). Notably, PCDH10 expression is increased in OECs derived from GDM-EPCs, which is associated with the inhibition of angiogenic function in fetal EPCs. Additionally, increased PCDH10 expression is correlated with the hypomethylation of the PCDH10 promoter. Our findings demonstrate that in utero exposure to GDM can induce angiogenic dysfunction in fetal EPCs through altered gene expression and epigenetic changes, consequently increasing the susceptibility to cardiovascular diseases in the offspring of GDM mothers.<\/jats:p>","DOI":"10.3390\/ijms242216082","type":"journal-article","created":{"date-parts":[[2023,11,9]],"date-time":"2023-11-09T03:42:08Z","timestamp":1699501328000},"page":"16082","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Impaired Angiogenic Function of Fetal Endothelial Progenitor Cells via PCDH10 in Gestational Diabetes Mellitus"],"prefix":"10.3390","volume":"24","author":[{"given":"Hayan","family":"Kwon","sequence":"first","affiliation":[{"name":"Department of Obstetrics and Gynecology, Institute of Women\u2019s Life Medical Science, Yonsei University College of Medicine, Seoul 03722, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6615-6401","authenticated-orcid":false,"given":"Yun Ji","family":"Jung","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Institute of Women\u2019s Life Medical Science, Yonsei University College of Medicine, Seoul 03722, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yeji","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Institute of Women\u2019s Life Medical Science, Yonsei University College of Medicine, Seoul 03722, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5393-0832","authenticated-orcid":false,"given":"Ga-Hyun","family":"Son","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Kangnam Sacred Heart Hospital, Hallym University Medical Center, Hallym University College of Medicine, Seoul 07441, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hyun Ok","family":"Kim","sequence":"additional","affiliation":[{"name":"Korea Cell-Based Artificial Blood Project, Regenerative Medicine Acceleration Foundation, Seoul 04512, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1694-8405","authenticated-orcid":false,"given":"Yong-Sun","family":"Maeng","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Institute of Women\u2019s Life Medical Science, Yonsei University College of Medicine, Seoul 03722, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3009-6325","authenticated-orcid":false,"given":"Ja-Young","family":"Kwon","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Institute of Women\u2019s Life Medical Science, Yonsei University College of Medicine, Seoul 03722, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,11,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"S251","DOI":"10.2337\/dc07-s225","article-title":"Summary and recommendations of the fifth international workshop-conference on gestational diabetes mellitus","volume":"30","author":"Metzger","year":"2007","journal-title":"Diabetes Care"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1007\/s11892-015-0699-x","article-title":"Prevalence of gestational diabetes and risk of progression to type 2 diabetes: A global perspective","volume":"16","author":"Zhu","year":"2016","journal-title":"Curr. Diab. Rep."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1038\/ajh.2008.326","article-title":"Intrauterine exposure to gestational diabetes, child adiposity, and blood pressure","volume":"22","author":"Wright","year":"2009","journal-title":"Am. J. Hypertens."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"e290","DOI":"10.1542\/peds.2004-1808","article-title":"Metabolic syndrome in childhood: Association with birth weight, maternal obesity, and gestational diabetes mellitus","volume":"115","author":"Boney","year":"2005","journal-title":"Pediatrics"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"3225","DOI":"10.1210\/jc.2005-0007","article-title":"Intrauterine exposure to diabetes is a determinant of hemoglobin a(1)c and systolic blood pressure in pima indian children","volume":"90","author":"Bunt","year":"2005","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"587","DOI":"10.1067\/mpd.2000.105129","article-title":"Correlations between the intrauterine metabolic environment and blood pressure in adolescent offspring of diabetic mothers","volume":"136","author":"Cho","year":"2000","journal-title":"J. Pediatr."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1007\/s11892-019-1267-6","article-title":"Hyperglycemia during pregnancy and long-term offspring outcomes","volume":"19","author":"Bianco","year":"2019","journal-title":"Curr. Diab. Rep."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1673","DOI":"10.2337\/db18-0123","article-title":"Placental DNA methylation adaptation to maternal glycemic response in pregnancy","volume":"67","author":"Cardenas","year":"2018","journal-title":"Diabetes"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1017\/S2040174414000038","article-title":"Placental lipoprotein lipase DNA methylation levels are associated with gestational diabetes mellitus and maternal and cord blood lipid profiles","volume":"5","author":"Houde","year":"2014","journal-title":"J. Dev. Orig. Health Dis."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"563","DOI":"10.1007\/s00441-017-2583-2","article-title":"Hyperglycemia impedes definitive endoderm differentiation of human embryonic stem cells by modulating histone methylation patterns","volume":"368","author":"Chen","year":"2017","journal-title":"Cell Tissue Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"664","DOI":"10.1161\/ATVBAHA.114.304730","article-title":"Gestational diabetes mellitus impairs fetal endothelial cell functions through a mechanism involving microrna-101 and histone methyltransferase enhancer of zester homolog-2","volume":"35","author":"Floris","year":"2015","journal-title":"Arter. Thromb. Vasc. Biol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1007\/s10157-006-0448-1","article-title":"Endothelial progenitor cells for postnatal vasculogenesis","volume":"11","author":"Eguchi","year":"2007","journal-title":"Clin. Exp. Nephrol."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Salybekov, A.A., Kobayashi, S., and Asahara, T. (2022). Characterization of endothelial progenitor cell: Past, present, and future. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23147697"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"848272","DOI":"10.1155\/2015\/848272","article-title":"Diabetes, endothelial dysfunction, and vascular repair: What should a diabetologist keep his eye on?","volume":"2015","author":"Altabas","year":"2015","journal-title":"Int. J. Endocrinol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1930","DOI":"10.1161\/CIRCRESAHA.116.308366","article-title":"Levels of circulating progenitor cells, cardiovascular outcomes and death: A meta-analysis of prospective observational studies","volume":"118","author":"Rigato","year":"2016","journal-title":"Circ. Res."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2666","DOI":"10.1210\/jc.2015-1687","article-title":"Circulating progenitor cell count predicts microvascular outcomes in type 2 diabetic patients","volume":"100","author":"Rigato","year":"2015","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"984","DOI":"10.4103\/1673-5374.250577","article-title":"Decreased numbers of circulating endothelial progenitor cells are associated with hyperglycemia in patients with traumatic brain injury","volume":"14","author":"Wei","year":"2019","journal-title":"Neural Regen. Res."},{"key":"ref_18","first-page":"1","article-title":"Fetal exposure to a diabetic intrauterine environment resulted in a failure of cord blood endothelial progenitor cell adaptation against chronic hypoxia","volume":"8","author":"Dincer","year":"2015","journal-title":"Stem Cells Cloning"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Sallam, N.A., Palmgren, V.A.C., Singh, R.D., John, C.M., and Thompson, J.A. (2018). Programming of vascular dysfunction in the intrauterine milieu of diabetic pregnancies. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19113665"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"419","DOI":"10.1007\/s10974-021-09607-9","article-title":"Organisational alteration of cardiac myofilament proteins by hyperglycaemia in mouse embryonic stem cell-derived cardiomyocytes","volume":"42","author":"Aboalgasm","year":"2021","journal-title":"J. Muscle Res. Cell Motil."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Dluski, D.F., Wolinska, E., and Skrzypczak, M. (2021). Epigenetic changes in gestational diabetes mellitus. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22147649"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"538474","DOI":"10.1155\/2012\/538474","article-title":"Impact of maternal diabetes on epigenetic modifications leading to diseases in the offspring","volume":"2012","author":"Vrachnis","year":"2012","journal-title":"Exp. Diabetes Res."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Slupecka-Ziemilska, M., Wychowanski, P., and Puzianowska-Kuznicka, M. (2020). Gestational diabetes mellitus affects offspring\u2019s epigenome. Is there a way to reduce the negative consequences?. Nutrients, 12.","DOI":"10.3390\/nu12092792"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"788","DOI":"10.1038\/pr.2015.269","article-title":"Gestational diabetes induces alterations of sirtuins in fetal endothelial cells","volume":"79","author":"Gui","year":"2016","journal-title":"Pediatr. Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"410","DOI":"10.1016\/j.placenta.2015.01.195","article-title":"Vitamin d rescues dysfunction of fetal endothelial colony forming cells from individuals with gestational diabetes","volume":"36","author":"Gui","year":"2015","journal-title":"Placenta"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2664","DOI":"10.2337\/db14-1709","article-title":"Epigenetic regulation of placenta-specific 8 contributes to altered function of endothelial colony-forming cells exposed to intrauterine gestational diabetes mellitus","volume":"64","author":"Blue","year":"2015","journal-title":"Diabetes"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1885","DOI":"10.1002\/jcp.25734","article-title":"Mesenchyme homeobox 2 enhances migration of endothelial colony forming cells exposed to intrauterine diabetes mellitus","volume":"232","author":"Gohn","year":"2017","journal-title":"J. Cell Physiol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"C502","DOI":"10.1152\/ajpcell.00137.2018","article-title":"Transgelin induces dysfunction of fetal endothelial colony-forming cells from gestational diabetic pregnancies","volume":"315","author":"Varberg","year":"2018","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Yadav, S.S., and Narayan, G. (2014). Role of robo4 signalling in developmental and pathological angiogenesis. BioMed Res. Int., 2014.","DOI":"10.1155\/2014\/683025"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"5210","DOI":"10.1167\/iovs-14-16184","article-title":"Slit2 promotes angiogenic activity via the robo1-vegfr2-erk1\/2 pathway in both in vivo and in vitro studies","volume":"56","author":"Li","year":"2015","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1007\/s10456-017-9592-3","article-title":"Slit2\/robo1 signaling is involved in angiogenesis of glomerular endothelial cells exposed to a diabetic-like environment","volume":"21","author":"Liu","year":"2018","journal-title":"Angiogenesis"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"696","DOI":"10.1210\/en.2017-00572","article-title":"Insulinlike growth factor-binding protein-1 improves vascular endothelial repair in male mice in the setting of insulin resistance","volume":"159","author":"Aziz","year":"2018","journal-title":"Endocrinology"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1016\/j.cytogfr.2019.03.005","article-title":"Insulin-like growth factor binding proteins and angiogenesis: From cancer to cardiovascular disease","volume":"46","author":"Slater","year":"2019","journal-title":"Cytokine Growth Factor Rev."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"901","DOI":"10.1101\/gad.291004","article-title":"The notch target genes hey1 and hey2 are required for embryonic vascular development","volume":"18","author":"Fischer","year":"2004","journal-title":"Genes Dev."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1186\/s13287-018-0945-7","article-title":"Role of notch1 in the arterial specification and angiogenic potential of mouse embryonic stem cell-derived endothelial cells","volume":"9","author":"Park","year":"2018","journal-title":"Stem Cell Res. Ther."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1070","DOI":"10.1038\/sj.onc.1209154","article-title":"Functional epigenetics identifies a protocadherin PCDH10 as a candidate tumor suppressor for nasopharyngeal, esophageal and multiple other carcinomas with frequent methylation","volume":"25","author":"Ying","year":"2006","journal-title":"Oncogene"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"747","DOI":"10.3892\/or.2015.4056","article-title":"PCDH10 inhibits cell proliferation of multiple myeloma via the negative regulation of the wnt\/beta-catenin\/bcl-9 signaling pathway","volume":"34","author":"Xu","year":"2015","journal-title":"Oncol. Rep."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"857","DOI":"10.1080\/15384101.2015.1004935","article-title":"PCDH10, a novel p53 transcriptional target in regulating cell migration","volume":"14","author":"Shi","year":"2015","journal-title":"Cell Cycle"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1289","DOI":"10.4161\/epi.26554","article-title":"Adaptations of placental and cord blood abca1 DNA methylation profile to maternal metabolic status","volume":"8","author":"Houde","year":"2013","journal-title":"Epigenetics"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1016\/j.clnesp.2017.12.006","article-title":"Mafos-gdm trial: Maternal fish oil supplementation in women with gestational diabetes and cord blood DNA methylation at insulin like growth factor-1 (igf-1) gene","volume":"23","author":"Dilli","year":"2018","journal-title":"Clin. Nutr. ESPEN"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1186\/s13148-017-0321-y","article-title":"Maternal intake of methyl-group donors affects DNA methylation of metabolic genes in infants","volume":"9","author":"Pauwels","year":"2017","journal-title":"Clin. Epigenetics"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1210\/jc.2018-01659","article-title":"Reduced insulin receptor expression and altered DNA methylation in fat tissues and blood of women with gdm and offspring","volume":"104","author":"Ott","year":"2019","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"108690","DOI":"10.1016\/j.diabres.2021.108690","article-title":"Exposure to gestational diabetes mellitus (gdm) alters DNA methylation in placenta and fetal cord blood","volume":"174","author":"Awamleh","year":"2021","journal-title":"Diabetes Res. Clin. Pract."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"807","DOI":"10.1038\/bjc.2013.351","article-title":"Epigenetic alteration: New insights moving from tissue to plasma\u2014The example of PCDH10 promoter methylation in colorectal cancer","volume":"109","author":"Danese","year":"2013","journal-title":"Br. J. Cancer"},{"key":"ref_45","first-page":"4462","article-title":"Aberrant promoter methylation of PCDH10 as a potential diagnostic and prognostic biomarker for patients with breast cancer","volume":"16","author":"Liu","year":"2018","journal-title":"Oncol. Lett."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"118","DOI":"10.3349\/ymj.2021.62.2.118","article-title":"Hotair induces methylation of PCDH10, a tumor suppressor gene, by regulating dnmt1 and sponging with mir-148b in gastric adenocarcinoma","volume":"62","author":"Seo","year":"2021","journal-title":"Yonsei Med. J."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"829","DOI":"10.1111\/j.1365-2141.2007.06512.x","article-title":"Frequent epigenetic silencing of protocadherin 10 by methylation in multiple haematologic malignancies","volume":"136","author":"Ying","year":"2007","journal-title":"Br. J. Haematol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"146","DOI":"10.1016\/j.preghy.2018.12.005","article-title":"Cd133+\/c-kit+lin(\u2212) endothelial progenitor cells in fetal circulation demonstrate impaired differentiation potency in severe preeclampsia","volume":"15","author":"Park","year":"2019","journal-title":"Pregnancy Hypertens."},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Kwon, H., Kwon, J.-Y., Song, J., and Maeng, Y.-S. (2021). Decreased lymphangiogenic activities and genes expression of cord blood lymphatic endothelial progenitor cells (vegfr3+\/pod+\/cd11b+ cells) in patient with preeclampsia. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22084237"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/22\/16082\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T21:19:26Z","timestamp":1760131166000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/22\/16082"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,11,8]]},"references-count":49,"journal-issue":{"issue":"22","published-online":{"date-parts":[[2023,11]]}},"alternative-id":["ijms242216082"],"URL":"https:\/\/doi.org\/10.3390\/ijms242216082","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,11,8]]}}}