{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T10:14:06Z","timestamp":1787825646923,"version":"build-2784847793"},"reference-count":85,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T00:00:00Z","timestamp":1782864000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100012818","name":"Comunidad de Madrid","doi-asserted-by":"crossref","award":["P2022\/BMD-7321"],"award-info":[{"award-number":["P2022\/BMD-7321"]}],"id":[{"id":"10.13039\/100012818","id-type":"DOI","asserted-by":"crossref"}]},{"award":["P2022\/BMD-7321"],"award-info":[{"award-number":["P2022\/BMD-7321"]}],"id":[{"id":"https:\/\/ror.org\/040scgh75","id-type":"ROR","asserted-by":"publisher"}]},{"name":"ProACapital"},{"name":"HALEKULANI"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Medical Sciences"],"abstract":"<jats:p>Background: Late-onset preeclampsia (LO-PE) is the most prevalent clinical phenotype of preeclampsia and, although traditionally considered less strongly associated with placental dysfunction than early-onset disease, increasing evidence supports the presence of relevant placental alterations. The extracellular matrix (ECM) is a key regulator of villous architecture, tissue mechanics, trophoblast behavior, vascular remodeling, and angiogenesis. This study aimed to characterize ECM remodeling in placentas from women with LO-PE. Patients and Methods: A prospective observational study was conducted in 111 pregnant women, including 68 with LO-PE and 43 healthy controls. Placental samples were collected immediately after delivery. Gene expression of elastogenesis-related markers, cross-linking enzymes, fibrillar collagens, matrix-remodeling regulators, and endothelial\u2013matrix signaling molecules was assessed by RT-qPCR. Protein expression was evaluated by immunohistochemistry. Differences between groups were analyzed using non-parametric tests with Benjamini\u2013Hochberg correction, and correlations among ECM markers were explored using Spearman analysis. Results: LO-PE placentas showed significantly increased expression of tropoelastin (TE), fibulin-4 (FBLN-4), fibulin-5 (FBLN-5), fibrillin-1 (FBN-1), lysyl oxidase (LOX), lysyl oxidase-like 1 (LOXL-1), collagen type I (COL-I), collagen type III (COL-III), and matrix metalloproteinase-2 (MMP-2) at both gene and protein levels. Conversely, gene and protein expression of tissue inhibitor of metalloproteinase-2 (TIMP-2) and epidermal growth factor-like domain 7 (EGFL7) showed a marked decrease in the placentas of pregnant women with LO-PE. These findings indicate enhanced elastogenesis, increased matrix cross-linking, greater fibrillar collagen deposition, and an imbalance in matrix turnover. Correlation analysis further suggested that, although the FBLN-4\/FBLN-5 axis remained preserved, LO-PE placentas displayed partial disruption of the broader ECM transcriptional network. Conclusions: LO-PE placentas exhibit a coordinated but dysregulated ECM remodeling phenotype involving elastic, collagenous, proteolytic, and endothelial\u2013matrix regulatory pathways. These alterations support ECM remodeling as a relevant biological feature of LO-PE placental pathophysiology.<\/jats:p>","DOI":"10.3390\/medsci14030364","type":"journal-article","created":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T08:19:02Z","timestamp":1782893942000},"page":"364","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Late-Onset Preeclampsia Is Linked to Extensive Remodeling of the Placental Extracellular Matrix"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6016-7855","authenticated-orcid":false,"given":"Cielo","family":"Garc\u00eda-Montero","sequence":"first","affiliation":[{"name":"Department of Medicine and Medical Specialities, Faculty of Medicine and Health Sciences, University of Alcal\u00e1, 28801 Alcal\u00e1 de Henares, Spain"},{"name":"Ram\u00f3n y Cajal Institute of Sanitary Research (IRYCIS), 28034 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tatiana","family":"Pekarek","sequence":"additional","affiliation":[{"name":"Department of Medicine and Medical Specialities, Faculty of Medicine and Health Sciences, University of Alcal\u00e1, 28801 Alcal\u00e1 de Henares, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"\u00d3scar","family":"Fraile-Martinez","sequence":"additional","affiliation":[{"name":"Department of Medicine and Medical Specialities, Faculty of Medicine and Health Sciences, University of Alcal\u00e1, 28801 Alcal\u00e1 de Henares, Spain"},{"name":"Ram\u00f3n y Cajal Institute of Sanitary Research (IRYCIS), 28034 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diego Liviu","family":"Boaru","sequence":"additional","affiliation":[{"name":"Department of Medicine and Medical Specialities, Faculty of Medicine and Health Sciences, University of Alcal\u00e1, 28801 Alcal\u00e1 de Henares, Spain"},{"name":"Ram\u00f3n y Cajal Institute of Sanitary Research (IRYCIS), 28034 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-8591-6116","authenticated-orcid":false,"given":"Patricia","family":"de Castro-Martinez","sequence":"additional","affiliation":[{"name":"Department of Medicine and Medical Specialities, Faculty of Medicine and Health Sciences, University of Alcal\u00e1, 28801 Alcal\u00e1 de Henares, Spain"},{"name":"Ram\u00f3n y Cajal Institute of Sanitary Research (IRYCIS), 28034 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beatriz","family":"Garc\u00eda-Gonz\u00e1lez","sequence":"additional","affiliation":[{"name":"Department of Medicine and Medical Specialities, Faculty of Medicine and Health Sciences, University of Alcal\u00e1, 28801 Alcal\u00e1 de Henares, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-6414-0843","authenticated-orcid":false,"given":"Marina","family":"Fanega-Fern\u00e1ndez","sequence":"additional","affiliation":[{"name":"Department of Medicine and Medical Specialities, Faculty of Medicine and Health Sciences, University of Alcal\u00e1, 28801 Alcal\u00e1 de Henares, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Coral","family":"Bravo","sequence":"additional","affiliation":[{"name":"Department of Public and Maternal and Child Health, School of Medicine, Complutense University of Madrid, 28040 Madrid, Spain"},{"name":"Department of Obstetrics and Gynecology, University Hospital Gregorio Mara\u00f1\u00f3n, 28007 Madrid, Spain"},{"name":"Health Research Institute Gregorio Mara\u00f1\u00f3n, 28009 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6320-2668","authenticated-orcid":false,"given":"Juan A.","family":"De Leon-Luis","sequence":"additional","affiliation":[{"name":"Department of Public and Maternal and Child Health, School of Medicine, Complutense University of Madrid, 28040 Madrid, Spain"},{"name":"Department of Obstetrics and Gynecology, University Hospital Gregorio Mara\u00f1\u00f3n, 28007 Madrid, Spain"},{"name":"Health Research Institute Gregorio Mara\u00f1\u00f3n, 28009 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0412-939X","authenticated-orcid":false,"given":"Raul","family":"Diaz-Pedrero","sequence":"additional","affiliation":[{"name":"Ram\u00f3n y Cajal Institute of Sanitary Research (IRYCIS), 28034 Madrid, Spain"},{"name":"Department of Surgery, Medical and Social Sciences, Faculty of Medicine and Health Sciences, University of Alcal\u00e1, 28801 Alcal\u00e1 de Henares, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Lopez-Gonzalez","sequence":"additional","affiliation":[{"name":"Ram\u00f3n y Cajal Institute of Sanitary Research (IRYCIS), 28034 Madrid, Spain"},{"name":"Department of Surgery, Medical and Social Sciences, Faculty of Medicine and Health Sciences, University of Alcal\u00e1, 28801 Alcal\u00e1 de Henares, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-1635-4254","authenticated-orcid":false,"given":"Moises","family":"Fernandez-Iba\u00f1ez","sequence":"additional","affiliation":[{"name":"Department of Medicine and Medical Specialities, Faculty of Medicine and Health Sciences, University of Alcal\u00e1, 28801 Alcal\u00e1 de Henares, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlota","family":"Castilla","sequence":"additional","affiliation":[{"name":"Department of Medicine and Medical Specialities, Faculty of Medicine and Health Sciences, University of Alcal\u00e1, 28801 Alcal\u00e1 de Henares, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvestra","family":"Barrena-Bl\u00e1zquez","sequence":"additional","affiliation":[{"name":"Ram\u00f3n y Cajal Institute of Sanitary Research (IRYCIS), 28034 Madrid, Spain"},{"name":"Department of Nursing and Physiotherapy, Faculty of Medicine and Health Sciences, University of Alcal\u00e1, 28801 Alcal\u00e1 de Henares, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2419-2476","authenticated-orcid":false,"given":"Julia","family":"Bujan","sequence":"additional","affiliation":[{"name":"Department of Medicine and Medical Specialities, Faculty of Medicine and Health Sciences, University of Alcal\u00e1, 28801 Alcal\u00e1 de Henares, Spain"},{"name":"Ram\u00f3n y Cajal Institute of Sanitary Research (IRYCIS), 28034 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0904-6198","authenticated-orcid":false,"given":"Natalio","family":"Garc\u00eda-Honduvilla","sequence":"additional","affiliation":[{"name":"Department of Medicine and Medical Specialities, Faculty of Medicine and Health Sciences, University of Alcal\u00e1, 28801 Alcal\u00e1 de Henares, Spain"},{"name":"Ram\u00f3n y Cajal Institute of Sanitary Research (IRYCIS), 28034 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1309-7510","authenticated-orcid":false,"given":"Melchor","family":"Alvarez-Mon","sequence":"additional","affiliation":[{"name":"Department of Medicine and Medical Specialities, Faculty of Medicine and Health Sciences, University of Alcal\u00e1, 28801 Alcal\u00e1 de Henares, Spain"},{"name":"Ram\u00f3n y Cajal Institute of Sanitary Research (IRYCIS), 28034 Madrid, Spain"},{"name":"Immune System Diseases-Rheumatology and Internal Medicine Service, University Hospital Pr\u00edncipe de Asturias, 28806 Alcal\u00e1 de Henares, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8389-258X","authenticated-orcid":false,"given":"Miguel A.","family":"Saez","sequence":"additional","affiliation":[{"name":"Department of Medicine and Medical Specialities, Faculty of Medicine and Health Sciences, University of Alcal\u00e1, 28801 Alcal\u00e1 de Henares, Spain"},{"name":"Ram\u00f3n y Cajal Institute of Sanitary Research (IRYCIS), 28034 Madrid, Spain"},{"name":"Pathological Anatomy Service, Central University Hospital of Defence-UAH Madrid, 28801 Alcal\u00e1 de Henares, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2588-1708","authenticated-orcid":false,"given":"Miguel A.","family":"Ortega","sequence":"additional","affiliation":[{"name":"Department of Medicine and Medical Specialities, Faculty of Medicine and Health Sciences, University of Alcal\u00e1, 28801 Alcal\u00e1 de Henares, Spain"},{"name":"Ram\u00f3n y Cajal Institute of Sanitary Research (IRYCIS), 28034 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,1]]},"reference":[{"key":"ref_1","first-page":"1402","article-title":"Pre-Eclampsia, Eclampsia, and Hypertension","volume":"2008","author":"Duley","year":"2008","journal-title":"BMJ Clin. Evid."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Kutllovci Hasani, K., Ajeti, N., and Goswami, N. (2025). Understanding Preeclampsia: Cardiovascular Pathophysiology, Histopathological Insights and Molecular Biomarkers. Med. Sci., 13.","DOI":"10.3390\/medsci13030154"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Fox, R., Kitt, J., Leeson, P., Aye, C.Y.L., and Lewandowski, A.J. (2019). Preeclampsia: Risk Factors, Diagnosis, Management, and the Cardiovascular Impact on the Offspring. J. Clin. Med., 8.","DOI":"10.3390\/jcm8101625"},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Socol, F.G., Bernad, E., Craina, M., Abu-Awwad, S.A., Bernad, B.C., Socol, I.D., Abu-Awwad, A., Farcas, S.S., Pop, D.L., and Gurgus, D. (2024). Health Impacts of Pre-Eclampsia: A Comprehensive Analysis of Maternal and Neonatal Outcomes. Medicina, 60.","DOI":"10.3390\/medicina60091486"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"F1315","DOI":"10.1152\/ajprenal.00071.2020","article-title":"Preeclampsia beyond Pregnancy: Long-Term Consequences for Mother and Child","volume":"318","author":"Turbeville","year":"2020","journal-title":"Am. J. Physiol. Ren. Physiol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"3496","DOI":"10.1038\/s41467-025-58437-7","article-title":"Predicting Interval from Diagnosis to Delivery in Preeclampsia Using Electronic Health Records","volume":"16","author":"Yang","year":"2025","journal-title":"Nat. Commun."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"4108271","DOI":"10.1155\/2019\/4108271","article-title":"Early- and Late-Onset Preeclampsia: A Comprehensive Cohort Study of Laboratory and Clinical Findings According to the New ISHHP Criteria","volume":"2019","author":"Babczyk","year":"2019","journal-title":"Int. J. Hypertens."},{"key":"ref_8","first-page":"4108271","article-title":"Maternal and Fetal Outcomes in Early-Onset vs. Late-Onset Preeclampsia: A Retrospective Study at a Tertiary Care Institute in India","volume":"18","author":"Harjai","year":"2026","journal-title":"Cureus"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"262","DOI":"10.3109\/10641950902777697","article-title":"Late Onset Preeclampsia Is Not an Innocuous Condition","volume":"29","author":"Kenneth","year":"2010","journal-title":"Hypertens. Pregnancy"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"771","DOI":"10.1097\/AOG.0000000000000472","article-title":"Maternal Morbidity Associated with Early-Onset and Late-Onset Preeclampsia","volume":"124","author":"Lisonkova","year":"2014","journal-title":"Obstet. Gynecol."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Erez, O., Romero, R., Maymon, E., Chaemsaithong, P., Done, B., Pacora, P., Panaitescu, B., Chaiworapongsa, T., Hassan, S.S., and Tarca, A.L. (2017). The Prediction of Late-Onset Preeclampsia: Results from a Longitudinal Proteomics Study. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0181468"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Ortega, M.A., Fraile-Mart\u00ednez, O., Garc\u00eda-Montero, C., S\u00e1ez, M.A., \u00c1lvarez-Mon, M.A., Torres-Carranza, D., \u00c1lvarez-Mon, M., Bujan, J., Garc\u00eda-Honduvilla, N., and Bravo, C. (2022). The Pivotal Role of the Placenta in Normal and Pathological Pregnancies: A Focus on Preeclampsia, Fetal Growth Restriction, and Maternal Chronic Venous Disease. Cells, 11.","DOI":"10.3390\/cells11030568"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"654","DOI":"10.4103\/ATMR.ATMR_143_25","article-title":"Placental Age-Mismatch in Early- and Late-Onset Pre-Eclampsia: A Systematic Review of Multi-Omics Evidence","volume":"2","author":"Andonotopo","year":"2025","journal-title":"J. Adv. Trends Med. Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.jri.2019.07.004","article-title":"The Two-Stage Placental Model of Preeclampsia: An Update","volume":"134\u2013135","author":"Staff","year":"2019","journal-title":"J. Reprod. Immunol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1002\/uog.13310","article-title":"Uterine Artery Doppler, Birth Weight and Timing of Onset of Pre-Eclampsia: Providing Insights into the Dual Etiology of Late-Onset Pre-Eclampsia","volume":"44","author":"Verlohren","year":"2014","journal-title":"Ultrasound Obstet. Gynecol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"498","DOI":"10.3109\/14767058.2011.591461","article-title":"Late-Onset Preeclampsia Is Associated with an Imbalance of Angiogenic and Anti-Angiogenic Factors in Patients with and without Placental Lesions Consistent with Maternal Underperfusion","volume":"25","author":"Soto","year":"2012","journal-title":"J. Matern. Fetal. Neonatal Med."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Garcia-Puente, L.M., Garc\u00eda-Montero, C., Fraile-Martinez, O., Bujan, J., De Le\u00f3n-Luis, J.A., Bravo, C., Rodr\u00edguez-Benitez, P., L\u00f3pez-Gonz\u00e1lez, L., D\u00edaz-Pedrero, R., and \u00c1lvarez-Mon, M. (2024). Exploring the Importance of Differential Expression of Autophagy Markers in Term Placentas from Late-Onset Preeclamptic Pregnancies. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25042029"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Ortega, M.A., Garcia-Puente, L.M., Fraile-Martinez, O., Pekarek, T., Garc\u00eda-Montero, C., Bujan, J., Pekarek, L., Barrena-Bl\u00e1zquez, S., Gragera, R., and Rodr\u00edguez-Rojo, I.C. (2024). Oxidative Stress, Lipid Peroxidation and Ferroptosis Are Major Pathophysiological Signatures in the Placental Tissue of Women with Late-Onset Preeclampsia. Antioxidants, 13.","DOI":"10.3390\/antiox13050591"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Garcia-Puente, L.M., Fraile-Martinez, O., Garc\u00eda-Montero, C., Bujan, J., De Le\u00f3n-Luis, J.A., Bravo, C., Rodr\u00edguez-Benitez, P., Pintado, P., Ruiz-Labarta, F.J., and \u00c1lvarez-Mon, M. (2023). Placentas from Women with Late-Onset Preeclampsia Exhibit Increased Expression of the NLRP3 Inflammasome Machinery. Biomolecules, 13.","DOI":"10.3390\/biom13111644"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Ortega, M.A., Pekarek, T., De Leon-Oliva, D., Boaru, D.L., Fraile-Martinez, O., Garc\u00eda-Montero, C., Bujan, J., Pekarek, L., Barrena-Bl\u00e1zquez, S., and Gragera, R. (2024). Placental Tissue Calcification and Its Molecular Pathways in Female Patients with Late-Onset Preeclampsia. Biomolecules, 14.","DOI":"10.3390\/biom14101237"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1186\/s12958-025-01348-5","article-title":"Extracellular Matrix and Pregnancy: Functions and Opportunities Caught in the Net","volume":"23","author":"Rossi","year":"2025","journal-title":"Reprod. Biol. Endocrinol."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Szukiewicz, D., Trojanowski, S., Wr\u00f3bel, E., Wojdasiewicz, P., and Szewczyk, G. (2025). Mechanosensing of Shear Stress and Uterine Spiral Artery Remodeling by Invasive Trophoblasts in Early Pregnancy. Int. J. Mol. Sci., 26.","DOI":"10.3390\/ijms26199565"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1163","DOI":"10.1177\/1535370220938741","article-title":"The Role of Extracellular Matrix in Normal and Pathological Pregnancy: Future Applications of Microphysiological Systems in Reproductive Medicine","volume":"245","author":"Pope","year":"2020","journal-title":"Exp. Biol. Med."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"208","DOI":"10.1007\/s00404-002-0314-7","article-title":"Elastic Fibres in the Human Placenta","volume":"267","author":"Barros","year":"2003","journal-title":"Arch. Gynecol. Obstet."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1007\/s004410050521","article-title":"Elastic Fibres Are an Essential Component of Human Placental Stem Villous Stroma and an Integrated Part of the Perivascular Contractile Sheath","volume":"283","author":"Graf","year":"1996","journal-title":"Cell Tissue Res."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"597","DOI":"10.1007\/s004290050307","article-title":"Increase of Segments of Elastic-Type Blood Vessel Walls in Fetal Placental Stem Villi during Pre-Eclampsia at Term","volume":"200","author":"Wilhelm","year":"1999","journal-title":"Anat. Embryol."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Ozsvar, J., Yang, C., Cain, S.A., Baldock, C., Tarakanova, A., and Weiss, A.S. (2021). Tropoelastin and Elastin Assembly. Front. Bioeng. Biotechnol., 9.","DOI":"10.3389\/fbioe.2021.643110"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"eabc1404","DOI":"10.1126\/sciadv.abc1404","article-title":"A Matricellular Protein Fibulin-4 Is Essential for the Activation of Lysyl Oxidase","volume":"6","author":"Noda","year":"2020","journal-title":"Sci. Adv."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1007\/s12079-009-0065-3","article-title":"Fibulin-5, an Integrin-Binding Matricellular Protein: Its Function in Development and Disease","volume":"3","author":"Yanagisawa","year":"2009","journal-title":"J. Cell Commun. Signal."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1007\/s00418-011-0784-4","article-title":"Fibulin-5 Expression in the Human Placenta","volume":"135","author":"Gauster","year":"2011","journal-title":"Histochem. Cell Biol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"556","DOI":"10.3892\/mmr.2021.12195","article-title":"An Increase in Elastogenic Components in the Placental Villi of Women with Chronic Venous Disease during Pregnancy Is Associated with Decreased EGFL7 Expression Level","volume":"24","author":"Ortega","year":"2021","journal-title":"Mol. Med. Rep."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1016\/j.semcdb.2018.07.016","article-title":"Fibrillin Microfibrils and Elastic Fibre Proteins: Functional Interactions and Extracellular Regulation of Growth Factors","volume":"89","author":"Thomson","year":"2019","journal-title":"Semin. Cell Dev. Biol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"686","DOI":"10.1177\/107155769500200504","article-title":"Localization of Fibrillin-1 in the Human Term Placenta","volume":"2","author":"Jacobson","year":"1995","journal-title":"J. Soc. Gynecol. Investig."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Jang, J.H. (2026). Extracellular Matrix in Human Disease and Therapy: From Pathogenic Remodeling to Biomaterial Platforms and Precision Diagnostics. Biomedicines, 14.","DOI":"10.3390\/biomedicines14010247"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1053\/plac.2000.0580","article-title":"Lysyl Oxidases: Expression in the Fetal Membranes and Placenta","volume":"22","author":"Hein","year":"2001","journal-title":"Placenta"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1038\/s12276-019-0211-9","article-title":"Downregulation of Lysyl Oxidase and Lysyl Oxidase-like Protein 2 Suppressed the Migration and Invasion of Trophoblasts by Activating the TGF-\u03b2\/Collagen Pathway in Preeclampsia","volume":"51","author":"Xu","year":"2019","journal-title":"Exp. Mol. Med."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"5","DOI":"10.26502\/fccm.92920302","article-title":"Regulation of Collagen I and Collagen III in Tissue Injury and Regeneration","volume":"7","author":"Singh","year":"2023","journal-title":"Cardiol. Cardiovasc. Med."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"2220","DOI":"10.7150\/ijbs.45586","article-title":"Collagen at the Maternal-Fetal Interface in Human Pregnancy","volume":"16","author":"Shi","year":"2020","journal-title":"Int. J. Biol. Sci."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"S645","DOI":"10.1016\/j.ajog.2025.08.094","article-title":"Placenta Accreta Spectrum: Disrupted Collagen Architecture at a Previous Scar Is a Defining Characteristic of Placental Adherence","volume":"233","author":"Jeong","year":"2026","journal-title":"Am. J. Obstet. Gynecol."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Nikolov, A., Popovski, N., and Hristova, I. (2020). Collagenases MMP-1, MMP-13, and Tissue Inhibitors TIMP-1, TIMP-2: Their Role in Healthy and Complicated Pregnancy and Potential as Preeclampsia Biomarkers\u2014A Brief Review. Appl. Sci., 10.","DOI":"10.3390\/app10217731"},{"key":"ref_41","first-page":"567","article-title":"Remodelling of Collagen Fibres in the Placentas of Women with Venous Insufficiency during Pregnancy","volume":"33","author":"Ortega","year":"2018","journal-title":"Histol. Histopathol."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Wolosowicz, M., Prokopiuk, S., and Kaminski, T.W. (2024). The Complex Role of Matrix Metalloproteinase-2 (MMP-2) in Health and Disease. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms252413691"},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Cabral-Pacheco, G.A., Garza-Veloz, I., la Rosa, C.C.D., Ramirez-Acu\u00f1a, J.M., Perez-Romero, B.A., Guerrero-Rodriguez, J.F., Martinez-Avila, N., and Martinez-Fierro, M.L. (2020). The Roles of Matrix Metalloproteinases and Their Inhibitors in Human Diseases. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21249739"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"108764","DOI":"10.1016\/j.pharmthera.2024.108764","article-title":"EGFL7: An Emerging Biomarker with Great Therapeutic Potential","volume":"266","author":"Fabian","year":"2025","journal-title":"Pharmacol. Ther."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1016\/j.mod.2014.04.001","article-title":"Novel Expression of EGFL7 in Placental Trophoblast and Endothelial Cells and Its Implication in Preeclampsia","volume":"133","author":"Lacko","year":"2014","journal-title":"Mech. Dev."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"e237","DOI":"10.1097\/AOG.0000000000003891","article-title":"Gestational Hypertension and Preeclampsia: ACOG Practice Bulletin, Number 222","volume":"135","author":"Espinoza","year":"2020","journal-title":"Obstet. Gynecol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"581","DOI":"10.1038\/nprot.2006.83","article-title":"The Single-Step Method of RNA Isolation by Acid Guanidinium Thiocyanate\u2013Phenol\u2013Chloroform Extraction: Twenty-Something Years On","volume":"1","author":"Chomczynski","year":"2006","journal-title":"Nat. Protoc."},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Ye, J., Coulouris, G., Zaretskaya, I., Cutcutache, I., Rozen, S., and Madden, T.L. (2012). Primer-BLAST: A Tool to Design Target-Specific Primers for Polymerase Chain Reaction. BMC Bioinform., 13.","DOI":"10.1186\/1471-2105-13-134"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"226","DOI":"10.2144\/04372ST03","article-title":"AutoDimer: A Screening Tool for Primer-Dimer and Hairpin Structures","volume":"37","author":"Vallone","year":"2004","journal-title":"Biotechniques"},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Awoyemi, T., Motta-Mejia, C., Zhang, W., Kouser, L., White, K., Kandzija, N., Alhamlan, F.S., Cribbs, A.P., Tannetta, D., and Mazey, E. (2021). Syncytiotrophoblast Extracellular Vesicles from Late-Onset Preeclampsia Placentae Suppress Pro-Inflammatory Immune Response in THP-1 Macrophages. Front. Immunol., 12.","DOI":"10.3389\/fimmu.2021.676056"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"5028","DOI":"10.7150\/thno.56141","article-title":"Distinct Placental Molecular Processes Associated with Early-Onset and Late-Onset Preeclampsia","volume":"11","author":"Ren","year":"2021","journal-title":"Theranostics"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1016\/j.placenta.2016.11.014","article-title":"Impact of Early- and Late-Onset Preeclampsia on Features of Placental and Newborn Vascular Health","volume":"49","author":"Herzog","year":"2017","journal-title":"Placenta"},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Yang, N., Wang, Q., Ding, B., Gong, Y., Wu, Y., Sun, J., Wang, X., Liu, L., Zhang, F., and Du, D. (2022). Expression Profiles and Functions of Ferroptosis-Related Genes in the Placental Tissue Samples of Early- and Late-Onset Preeclampsia Patients. BMC Pregnancy Childbirth, 22.","DOI":"10.1186\/s12884-022-04423-6"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"S176","DOI":"10.1016\/j.ajog.2025.01.041","article-title":"Placenta at Single-Cell Resolution in Early and Late Preeclampsia: Insights and Clinical Implications","volume":"232","author":"Solt","year":"2025","journal-title":"Am. J. Obstet. Gynecol."},{"key":"ref_55","first-page":"e25189","article-title":"Large-Scale Proteomics Reveals New Candidate Biomarkers for Late-Onset Preeclampsia","volume":"83","author":"Andresen","year":"2025","journal-title":"Hypertension"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"6751456","DOI":"10.1155\/2022\/6751456","article-title":"Placental Tissues as Biomaterials in Regenerative Medicine","volume":"2022","author":"Roy","year":"2022","journal-title":"BioMed Res. Int."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1093\/molehr\/gau089","article-title":"Elastin-Derived Peptides Stimulate Trophoblast Migration and Invasion: A Positive Feedback Loop to Enhance Spiral Artery Remodelling","volume":"21","author":"Desforges","year":"2015","journal-title":"Mol. Hum. Reprod."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"365","DOI":"10.1042\/EBC20180052","article-title":"Recent Updates on the Molecular Network of Elastic Fiber Formation","volume":"63","author":"Shin","year":"2019","journal-title":"Essays Biochem."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"24553","DOI":"10.1074\/jbc.M109.019364","article-title":"Differential Regulation of Elastic Fiber Formation by Fibulin-4 and -5","volume":"284","author":"Choudhury","year":"2009","journal-title":"J. Biol. Chem."},{"key":"ref_60","first-page":"227","article-title":"An Increase of Elastic Tissue Fibers in Blood Vessel Walls of Placental Stem Villi and Differences in the Thickness of Blood Vessel Walls in Third Trimester Pre-Eclampsia Pregnancies","volume":"5","author":"Baran","year":"2009","journal-title":"Cent. Eur. J. Med."},{"key":"ref_61","first-page":"165961","article-title":"Oxidative Stress and Mitochondrial Dysfunction in Early-Onset and Late-Onset Preeclampsia","volume":"1866","author":"Chiarello","year":"2020","journal-title":"Biochim. Biophys. Acta (BBA)\u2014Mol. Basis Dis."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"dev181263","DOI":"10.1242\/dev.181263","article-title":"Low Oxygen Enhances Trophoblast Column Growth by Potentiating Differentiation of the Extravillous Lineage and Promoting LOX Activity","volume":"147","author":"Treissman","year":"2020","journal-title":"Development"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1042\/EBC20180050","article-title":"Lysyl Oxidases: From Enzyme Activity to Extracellular Matrix Cross-Links","volume":"63","author":"Vallet","year":"2019","journal-title":"Essays Biochem."},{"key":"ref_64","doi-asserted-by":"crossref","unstructured":"Andonotopo, W., Nyoman, I., Sanjaya, H., Dewantiningrum, J., Besari, M., Pramono, A., and Adrianes Bachnas, M. (2025). Preeclampsia and Placental Stiffness: A Systematic Review of Elastography as a Predictive Tool. Res. Sq.","DOI":"10.21203\/rs.3.rs-8237187\/v1"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"683","DOI":"10.1016\/j.ajpath.2017.11.008","article-title":"Fibrosis in Preeclamptic Placentas Is Associated with Stromal Fibroblasts Activated by the Transforming Growth Factor-\u03921 Signaling Pathway","volume":"188","author":"Asanoma","year":"2018","journal-title":"Am. J. Pathol."},{"key":"ref_66","doi-asserted-by":"crossref","unstructured":"Feng, Y., Chen, X., Wang, H., Chen, X., Lan, Z., Li, P., Cao, Y., Liu, M., Lv, J., and Chen, Y. (2021). Collagen I Induces Preeclampsia-Like Symptoms by Suppressing Proliferation and Invasion of Trophoblasts. Front. Endocrinol., 12.","DOI":"10.3389\/fendo.2021.664766"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1016\/S0065-1281(11)80308-9","article-title":"Participation of Collagen Types I, III, IV, V, and Fibronectin in the Formation of Villi Fibrosis in Human Term Placenta","volume":"89","author":"Rukosuev","year":"1990","journal-title":"Acta Histochem."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1530\/rep.1.00283","article-title":"Dynamic Expression of Matrix Metalloproteinases (MMP-2, -9 and -14) and the Tissue Inhibitors of MMPs (TIMP-1, -2 and -3) at the Implantation Site during Tubal Pregnancy","volume":"129","author":"Bai","year":"2005","journal-title":"Reproduction"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"1127","DOI":"10.1016\/S0024-3205(00)00416-1","article-title":"Quantitative Analysis of Matrix Metalloproteinases-2 and -9, and Their Tissue Inhibitors-1 and -2 in Human Placenta throughout Gestation","volume":"66","author":"Niu","year":"2000","journal-title":"Life Sci."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1016\/bs.pmbts.2017.04.001","article-title":"Matrix Metalloproteinases in Normal Pregnancy and Preeclampsia","volume":"148","author":"Chen","year":"2017","journal-title":"Prog. Mol. Biol. Transl. Sci."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1016\/j.preghy.2015.03.001","article-title":"Positive Correlations between Circulating Adiponectin and MMP2 in Preeclampsia Pregnant","volume":"5","author":"Eleuterio","year":"2015","journal-title":"Pregnancy Hypertens."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"8369645","DOI":"10.1155\/2020\/8369645","article-title":"Matrix Metalloproteinases MMP-2 and MMP-9 Occupy a New Role in Severe Preeclampsia","volume":"2020","author":"Timokhina","year":"2020","journal-title":"J. Pregnancy"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"6432426","DOI":"10.1155\/2017\/6432426","article-title":"Altered Maternal Serum Matrix Metalloproteinases MMP-2, MMP-3, MMP-9, and MMP-13 in Severe Early- and Late-Onset Preeclampsia","volume":"2017","author":"Laskowska","year":"2017","journal-title":"BioMed Res. Int."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"103783","DOI":"10.1016\/j.jpet.2025.103783","article-title":"Matrix Metalloproteinases and Their Association with Preeclampsia\/Eclampsia with Maternal Age: A Potential Link to Cardiovascular Disease in Later Life","volume":"393","author":"Taherkhani","year":"2026","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1186\/1477-7827-7-85","article-title":"Matrix metalloproteinase-2 is elevated in midtrimester amniotic fluid prior to the development of preeclampsia","volume":"7","author":"Lavee","year":"2009","journal-title":"Reprod. Biol. Endocrinol."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"42755","DOI":"10.31083\/CEOG42755","article-title":"Maternal Plasma Levels of MMP-2, MMP-3, MMP-9, TIMP-1, and TIMP-2 as Predictive Biomarkers of Preeclampsia","volume":"52","author":"Nguyen","year":"2025","journal-title":"Clin. Exp. Obstet. Gynecol."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"662","DOI":"10.1177\/0960327111431706","article-title":"Altered Expressions of MMP-2, MMP-9, and TIMP-2 in Placentas from Women Exposed to Lead","volume":"31","author":"Sanin","year":"2012","journal-title":"Hum. Exp. Toxicol."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"435","DOI":"10.1093\/molehr\/gav006","article-title":"Epidermal Growth Factor-like Domain 7 Promotes Migration and Invasion of Human Trophoblast Cells through Activation of MAPK, PI3K and NOTCH Signaling Pathways","volume":"21","author":"Massimiani","year":"2015","journal-title":"Mol. Hum. Reprod."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/j.trsl.2018.12.004","article-title":"Increased Circulating Levels of Epidermal Growth Factor-like Domain 7 in Pregnant Women Affected by Preeclampsia","volume":"207","author":"Massimiani","year":"2019","journal-title":"Transl. Res."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1007\/s13224-022-01697-w","article-title":"Evaluation Of Epidermal Growth Factor-Like Domain (EGFL7) mRNA Expression and its Protein Level in Preeclampsia","volume":"73","author":"Salah","year":"2023","journal-title":"J. Obstet. Gynaecol. India"},{"key":"ref_81","first-page":"2469","article-title":"Altered Feto-Placental Vascularization, Feto-Placental Malperfusion and Fetal Growth Restriction in Mice with Egfl7 Loss of Function","volume":"144","author":"Lacko","year":"2017","journal-title":"Development"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1016\/j.matbio.2014.02.004","article-title":"Fibulin-4 and Fibulin-5 in Elastogenesis and beyond: Insights from Mouse and Human Studies","volume":"37","author":"Papke","year":"2014","journal-title":"Matrix Biol."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"19029","DOI":"10.1073\/pnas.0908268106","article-title":"Fibulin-4 Conducts Proper Elastogenesis via Interaction with Cross-Linking Enzyme Lysyl Oxidase","volume":"106","author":"Horiguchi","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1038\/nrg2918","article-title":"Network Medicine: A Network-Based Approach to Human Disease","volume":"12","author":"Gulbahce","year":"2011","journal-title":"Nat. Rev. Genet."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"e1489","DOI":"10.1002\/wsbm.1489","article-title":"Molecular Networks in Network Medicine: Development and Applications","volume":"12","author":"Silverman","year":"2020","journal-title":"Wiley Interdiscip. Rev. Syst. Biol. Med."}],"container-title":["Medical Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-3271\/14\/3\/364\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,3]],"date-time":"2026-07-03T04:28:39Z","timestamp":1783052919000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-3271\/14\/3\/364"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,1]]},"references-count":85,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2026,7]]}},"alternative-id":["medsci14030364"],"URL":"https:\/\/doi.org\/10.3390\/medsci14030364","relation":{},"ISSN":["2076-3271"],"issn-type":[{"value":"2076-3271","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,1]]}}}