{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T01:17:16Z","timestamp":1760059036693,"version":"build-2065373602"},"reference-count":47,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2025,5,16]],"date-time":"2025-05-16T00:00:00Z","timestamp":1747353600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"King Saud University","award":["RSP2025R97"],"award-info":[{"award-number":["RSP2025R97"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Recurrent spontaneous miscarriage (RSM) is defined as the loss of three or more clinically recognized pregnancies before 20 weeks of gestation. Angiogenesis, a crucial process in early pregnancy, is regulated by vascular endothelial growth factor (VEGF), a protein that plays a pivotal role in successful pregnancy. Disruptions in vascular development, such as those due to variations in VEGF gene expression, may contribute to infertility and pregnancy complications. Therefore, there is a need for more studies that show the effect of VEGF on RSM. This study investigated the impact of VEGF gene polymorphisms on RSM in Saudi women. Blood samples were collected from 200 Saudi women (100 cases with RSM and 100 controls). DNA was extracted from the buffy coat and analyzed for VEGF polymorphisms (rs10434, rs3025053, rs699947, rs2010963, rs833061, and rs25648) using TaqMan Real-Time PCR. Plasma VEGF levels were measured using the Human VEGF ELISA Kit. There was no significant association between rs10434, rs833061, and rs25648 and RSM. However, rs2010963, rs3025053, and rs699947 were significantly associated with an increased risk of miscarriage (p &lt; 0.05). Furthermore, VEGF concentrations were significantly lower in the RSM case group (both pregnant and non-pregnant) compared to the control group (p &lt; 0.05). VEGF polymorphisms, along with reduced VEGF serum levels, are associated with an increased risk of RSM in Saudi women. Further studies are needed to explore the underlying mechanisms and potential therapeutic targets.<\/jats:p>","DOI":"10.3390\/ijms26104757","type":"journal-article","created":{"date-parts":[[2025,5,16]],"date-time":"2025-05-16T05:11:57Z","timestamp":1747372317000},"page":"4757","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Genetic Polymorphisms of Vascular Endothelial Growth Factor and Their Impact on Recurrent Spontaneous Miscarriage in Saudi Women"],"prefix":"10.3390","volume":"26","author":[{"given":"Wadha Khalid","family":"Al-Qahtani","sequence":"first","affiliation":[{"name":"Department of Zoology, College of Science, King Saud University, Riyadh 11451, Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4546-6061","authenticated-orcid":false,"given":"Afrah Fahad","family":"Alkhuriji","sequence":"additional","affiliation":[{"name":"Department of Zoology, College of Science, King Saud University, Riyadh 11451, Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zeneb Ahmed","family":"Babay","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynaecology, King Khalid University Hospital, King Saud University, Riyadh 11461, Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aaishah Mohammed Hussain","family":"Kaabi","sequence":"additional","affiliation":[{"name":"Department of Biology, College of Science, Qassim University, Buraidah 51452, Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1760-8405","authenticated-orcid":false,"given":"Nawal M.","family":"Al-Malahi","sequence":"additional","affiliation":[{"name":"Department of Zoology, College of Science, King Saud University, Riyadh 11451, Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jamilah Obaid","family":"Alshammari","sequence":"additional","affiliation":[{"name":"Department of Zoology, College of Science, King Saud University, Riyadh 11451, Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,5,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2471","DOI":"10.1016\/j.fertnstert.2011.03.010","article-title":"Effect of the functional VEGFA\u2212 583C\/T variant on vascular endothelial growth factor levels and the risk of recurrent spontaneous miscarriage","volume":"95","author":"Mustafa","year":"2011","journal-title":"Fertil. Steril."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"101483","DOI":"10.1016\/j.genrep.2021.101483","article-title":"Abnormal angiogenesis associated with HIF-1\u03b1\/VEGF signaling pathway in recurrent miscarriage along with therapeutic goals","volume":"26","author":"Taghizadeh","year":"2022","journal-title":"Gene Rep."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Abu-Ghazaleh, N., Brennecke, S., Murthi, P., and Karanam, V. (2023). Association of vascular endothelial growth factors (VEGFs) with recurrent miscarriage: A systematic review of the literature. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24119449"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1136\/postgradmedj-2014-132672","article-title":"Recurrent miscarriage: Causes, evaluation and management","volume":"91","year":"2015","journal-title":"Postgrad. Med. J."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"866","DOI":"10.1093\/humupd\/dmab010","article-title":"Maternal germline factors associated with aneuploid pregnancy loss: A systematic review","volume":"27","author":"Blyth","year":"2021","journal-title":"Hum. Reprod. Update"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"e13226","DOI":"10.1111\/aji.13226","article-title":"Causes of recurrent miscarriage after spontaneous pregnancy and after in vitro fertilization","volume":"83","author":"Bilibio","year":"2020","journal-title":"Am. J. Reprod. Immunol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"97.e1","DOI":"10.1016\/j.ajog.2020.07.012","article-title":"Week-by-week alcohol consumption in early pregnancy and spontaneous abortion risk: A prospective cohort study","volume":"224","author":"Sundermann","year":"2021","journal-title":"Am. J. Obstet. Gynecol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1658","DOI":"10.1016\/S0140-6736(21)00682-6","article-title":"Miscarriage matters: The epidemiological, physical, psychological, and economic costs of early pregnancy loss","volume":"397","author":"Quenby","year":"2021","journal-title":"Lancet"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Guo, X., Yi, H., Li, T.C., Wang, Y., Wang, H., and Chen, X. (2021). Role of vascular endothelial growth factor (VEGF) in human embryo implantation: Clinical implications. Biomolecules, 11.","DOI":"10.3390\/biom11020253"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"100606","DOI":"10.1016\/j.genrep.2020.100606","article-title":"The association of vascular endothelial growth factor polymorphism (rs699947) with diabetic foot ulcer and oxidative status","volume":"19","author":"Ahmed","year":"2020","journal-title":"Gene Rep."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"665","DOI":"10.47162\/RJME.61.3.04","article-title":"The role of mediating factors involved in angiogenesis during implantation","volume":"61","author":"Boldeanu","year":"2020","journal-title":"Rom. J. Morphol. Embryol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1007\/s00404-021-06072-0","article-title":"Polymorphisms of vascular endothelial growth factor and recurrent implantation failure: A systematic review and meta-analysis","volume":"304","author":"Zeng","year":"2021","journal-title":"Arch. Gynecol. Obstet."},{"key":"ref_13","first-page":"3","article-title":"Is there an Association Between-2549 Insertion\/Deletion Polymorphisms in the Promotor Region of the Gene Encoding for VEGFA as a Risk Factor and the Idiopathic Recurrent Spontaneous Miscarriage in a Sample of Jordanian Women","volume":"106","author":"Azzam","year":"2020","journal-title":"Prensa Med. Argent (Genet.)"},{"key":"ref_14","first-page":"41","article-title":"Different polymorphisms of vascular endothelial growth factor gene in patients with pre-eclampsia among the Iranian women population","volume":"14","author":"Niktalab","year":"2020","journal-title":"Int. J. Fertil. Steril."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"176","DOI":"10.1089\/gtmb.2023.0628","article-title":"VEGF-2578C\/A,-460T\/C polymorphisms and gastrointestinal tract cancer risk: An updated meta-analysis","volume":"28","author":"Mahajan","year":"2024","journal-title":"Genet. Test. Mol. Biomark."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"201168","DOI":"10.1016\/j.humgen.2023.201168","article-title":"Prognostic impact of serum vascular endothelial growth factor and VEGF gene polymorphism (rs2010963) in breast cancer patients","volume":"36","author":"Naidany","year":"2023","journal-title":"Hum. Gen."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2348","DOI":"10.47391\/JPMA.6072","article-title":"Association of vascular endothelial growth factor a gene (VEGFA) polymorphisms, rs699947 and rs1570360, with diabetic retinopathy and altered VEGF secretion in the Pakistani patients with type 2 diabetes mellitus: A casecontrol study","volume":"73","author":"Qayyum","year":"2023","journal-title":"J. Pak. Med. Assoc."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2382","DOI":"10.1210\/jc.2017-00437","article-title":"Pregnancy augments VEGF-stimulated in vitro angiogenesis and vasodilator (NO and H2S) production in human uterine artery endothelial cells","volume":"102","author":"Zhang","year":"2017","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_19","first-page":"455","article-title":"Vascular endothelial growth factor (VEGF)-key factor in normal and pathological angiogenesis","volume":"59","author":"Melincovici","year":"2018","journal-title":"Rom. J. Morphol. Embryol."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Mamer, S.B., Wittenkeller, A., and Imoukhuede, P. (2020). VEGF-A splice variants bind VEGFRs with differential affinities. Sci. Rep., 10.","DOI":"10.1038\/s41598-020-71484-y"},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Pang, L., Wei, Z., Li, O., Huang, R., Qin, J., Chen, H., Fan, X., and Chen, Z.-J. (2013). An increase in vascular endothelial growth factor (VEGF) and VEGF soluble receptor-1 (sFlt-1) are associated with early recurrent spontaneous abortion. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0075759"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1639","DOI":"10.1007\/s10815-017-1023-2","article-title":"The role of angiogenic markers in adverse perinatal outcomes: Fresh versus frozen embryo transfers","volume":"34","author":"Woo","year":"2017","journal-title":"J. Assist. Reprod. Genet."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"738","DOI":"10.1080\/00016340802158321","article-title":"Is serum-soluble vascular endothelial growth factor receptor-1 of importance in unexplained infertility?","volume":"87","author":"Isaksson","year":"2008","journal-title":"Acta Obstet. Gynecol. Scand."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"222","DOI":"10.1016\/j.cyto.2018.08.026","article-title":"Assessment of potential biomarkers of pre-receptive and receptive endometrium in uterine fluid and a functional evaluation of the potential role of CSF3 in fertility","volume":"111","author":"Edgell","year":"2018","journal-title":"Cytokine"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2680","DOI":"10.1242\/dev.106591","article-title":"Vegfd can compensate for loss of Vegfc in zebrafish facial lymphatic sprouting","volume":"141","author":"Astin","year":"2014","journal-title":"Development"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2167","DOI":"10.1172\/JCI83967","article-title":"Proteolytic activation defines distinct lymphangiogenic mechanisms for VEGFC and VEGFD","volume":"126","author":"Bui","year":"2016","journal-title":"J. Clin. Investig."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Zhou, Y., Zhu, X., Cui, H., Shi, J., Yuan, G., Shi, S., and Hu, Y. (2021). The role of the VEGF family in coronary heart disease. Front. Cardiovasc. Med., 8.","DOI":"10.3389\/fcvm.2021.738325"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1248","DOI":"10.1016\/j.cell.2019.01.021","article-title":"VEGF in signaling and disease: Beyond discovery and development","volume":"176","author":"Apte","year":"2019","journal-title":"Cell"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2520","DOI":"10.12659\/MSM.891394","article-title":"rs833061 and rs699947 on promoter gene of vascular endothelial growth factor (VEGF) and associated lung cancer susceptibility and survival: A meta-analysis","volume":"20","author":"Tu","year":"2014","journal-title":"Med. Sci. Monit."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"An, H.J., Kim, J.H., Ahn, E.H., Kim, Y.R., Kim, J.O., Park, H.S., Ryu, C.S., Kim, E.-G., Cho, S.H., and Lee, W.S. (2019). 3\u2032-UTR polymorphisms in the vascular endothelial growth factor gene (VEGF) contribute to susceptibility to recurrent pregnancy loss (RPL). Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20133319"},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Garc\u00eda-Closas, M., Malats, N., Real, F.X., Yeager, M., Welch, R., Silverman, D., Kogevinas, M., Dosemeci, M., Figueroa, J., and Chatterjee, N. (2007). Large-scale evaluation of candidate genes identifies associations between VEGF polymorphisms and bladder cancer risk. PLoS Genet., 3.","DOI":"10.1371\/journal.pgen.0030029"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1247","DOI":"10.1002\/ijc.28772","article-title":"VEGF and VEGFR genotyping in the prediction of clinical outcome for HCC patients receiving sorafenib: The ALICE-1 study","volume":"135","author":"Scartozzi","year":"2014","journal-title":"Int. J. Cancer"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1111\/jog.14192","article-title":"Association of vascular endothelial growth factor A polymorphisms and aberrant expression of connexin 43 and VEGFA with idiopathic recurrent spontaneous miscarriage","volume":"46","author":"Sajjadi","year":"2020","journal-title":"J. Obstet. Gynaecol. Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1035","DOI":"10.1016\/j.rbmo.2021.08.009","article-title":"Implications of VEGF gene sequence variations and its expression in recurrent pregnancy loss","volume":"43","author":"Amin","year":"2021","journal-title":"Reprod. Biomed. Online"},{"key":"ref_35","first-page":"51","article-title":"Study of genetic polymorphisms of Vascular Endothelial Growth Factor in women with recurrent abortion","volume":"9","author":"Bedairy","year":"2014","journal-title":"J. Pharm. Biol. Sci."},{"key":"ref_36","first-page":"342","article-title":"Association of rs1570360 and rs2010963 in VEGF and rs2279744 in the MDM2 gene with Recurrent Implantation Failure in Iranian Women","volume":"27","author":"Elmi","year":"2023","journal-title":"JBRA Assist. Reprod."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"e3048","DOI":"10.1002\/jgm.3048","article-title":"Association of genetic polymorphisms in VEGF-460,-7 and-583 and hematocrit level with the development of idiopathic recurrent pregnancy loss and a meta-analysis","volume":"20","author":"Jung","year":"2018","journal-title":"J. Gene Med."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"190","DOI":"10.1016\/j.rbmo.2015.10.010","article-title":"Genetic variants of vascular endothelial growth factor are associated with recurrent implantation failure in Korean women","volume":"32","author":"Jung","year":"2016","journal-title":"Reprod. Biomed. Online"},{"key":"ref_39","first-page":"88","article-title":"Fetal Vegf genotype is more important for abortion risk than mother genotype","volume":"3","author":"Yalcintepe","year":"2014","journal-title":"Int. J. Mol. Cell Med."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"2628","DOI":"10.1093\/humrep\/det308","article-title":"Relationship between VEGFA polymorphisms and serum VEGF protein levels and recurrent spontaneous miscarriage","volume":"28","author":"Almawi","year":"2013","journal-title":"Hum. Reprod."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1007\/s13224-018-1097-5","article-title":"Case control study to compare serum vascular endothelial growth factor (VEGF) level in women with recurrent pregnancy loss (RPL) compared to women with term pregnancy","volume":"69","author":"Gupta","year":"2019","journal-title":"J. Obstet. Gynaecol. India"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1244","DOI":"10.1111\/j.1600-0412.2011.01186.x","article-title":"A longitudinal study of plasma levels of soluble fms-like tyrosine kinase 1 (sFlt1), placental growth factor (PlGF), sFlt1: PlGF ratio and vascular endothelial growth factor (VEGF-A) in normal pregnancy","volume":"90","author":"Palm","year":"2011","journal-title":"Acta Obstet. Gynecol. Scand."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1111\/j.1471-0528.1997.tb11050.x","article-title":"Suppression of serum vascular endothelial growth factor immunoreactivity in normal pregnancy and in pre-eclampsia","volume":"104","author":"Lyall","year":"1997","journal-title":"Br. J. Obstet. Gynaecol."},{"key":"ref_44","first-page":"1259","article-title":"Maternal plasma levels of vascular endothelial growth factor and interleukin-6 in the term-pregnant and non-pregnant rats","volume":"14","year":"2018","journal-title":"Anim. Reprod. (AR)"},{"key":"ref_45","first-page":"219","article-title":"Association of growth factors genes with miscarriage","volume":"19","author":"Marakhovskaya","year":"2018","journal-title":"J. Reprod. Infertil."},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Braile, M., Marcella, S., Cristinziano, L., Galdiero, M.R., Modestino, L., Ferrara, A.L., Varricchi, G., Marone, G., and Loffredo, S. (2020). VEGF-A in cardiomyocytes and heart diseases. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21155294"},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Zhang, A., Fang, H., Chen, J., He, L., and Chen, Y. (2020). Role of VEGF-A and LRG1 in abnormal angiogenesis associated with diabetic nephropathy. Front. Physiol., 11.","DOI":"10.3389\/fphys.2020.01064"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/10\/4757\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T17:33:37Z","timestamp":1760031217000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/10\/4757"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,5,16]]},"references-count":47,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2025,5]]}},"alternative-id":["ijms26104757"],"URL":"https:\/\/doi.org\/10.3390\/ijms26104757","relation":{},"ISSN":["1422-0067"],"issn-type":[{"type":"electronic","value":"1422-0067"}],"subject":[],"published":{"date-parts":[[2025,5,16]]}}}