{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,6]],"date-time":"2026-02-06T03:25:06Z","timestamp":1770348306609,"version":"3.49.0"},"reference-count":69,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2025,3,9]],"date-time":"2025-03-09T00:00:00Z","timestamp":1741478400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Instituto de Salud Carlos III","award":["Estatal de I + D + I 2020\u20132027"],"award-info":[{"award-number":["Estatal de I + D + I 2020\u20132027"]}]},{"name":"European Development Regional Fund","award":["Estatal de I + D + I 2020\u20132027"],"award-info":[{"award-number":["Estatal de I + D + I 2020\u20132027"]}]},{"name":"P2022\/BMD-7321 (Comunidad de Madrid) and ProACapital-Fundaci\u00f3n Starlite, Halekulani S.L. and MJR","award":["Estatal de I + D + I 2020\u20132027"],"award-info":[{"award-number":["Estatal de I + D + I 2020\u20132027"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JPM"],"abstract":"<jats:p>Background: Chronic venous disease (CVD) is a vascular disorder common among pregnant women, due to the impairment in the venous function associated with the mechanical, hemodynamical, and hormonal changes that occur during pregnancy. CVD is linked to venous hypertension, inflammation, oxidative stress, and hypoxia, which alter placental structure and function, as demonstrated in previous works. The placenta fulfills several roles in fetal development and maternal well-being by mediating nutrient exchange; acting as a mechanical, chemical, and immunological shield; and producing essential hormones, making it crucial to investigate the effects of CVD in this organ. Patients and methods: This work specifically analyzes the gene expression of circadian markers (CLOCK, BMAL1, PER1, and PER2), epigenetic regulators (HAT1 and associated molecules like histones H3, H4, RBBP7, and ASF1), and the anti-aging protein KLOTHO in placental tissue of pregnant women with CVD (CVD-PW, N = 98) compared to healthy pregnant controls (HC-PW, N = 82), using RT-qPCR and immunohistochemistry (IHC) to determine protein expression. Results: Our study demonstrates that the placentas of CVD-PW exhibit the reduced gene and protein levels of circadian regulators (clock, bmal1, per1, and per2), increased expression of hat1 and related proteins (h3, h4, rbbp7, and asf1), and decreased klotho expression, indicative of accelerated aging. Conclusions: These findings highlight profound molecular disturbances in the placentas of women with CVD, offering insights into the disease\u2019s pathophysiology and potential implications for maternofetal well-being. While this study deepens our understanding of the relationship between CVD and placental dysfunction, further research is required to fully elucidate these mechanisms and their long-term effects.<\/jats:p>","DOI":"10.3390\/jpm15030107","type":"journal-article","created":{"date-parts":[[2025,3,10]],"date-time":"2025-03-10T05:46:52Z","timestamp":1741585612000},"page":"107","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Dysregulation of Circadian Markers, HAT1 and Associated Epigenetic Proteins, and the Anti-Aging Protein KLOTHO in Placenta of Pregnant Women with Chronic Venous Disease"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4494-6397","authenticated-orcid":false,"given":"Oscar","family":"Fraile-Martinez","sequence":"first","affiliation":[{"name":"Department of Medicine and Medical Specialities, Faculty of Medicine and Health Sciences, University of Alcal\u00e1, Networking Research Center on for Liver and Digestive Diseases (CIBEREHD), 28801 Alcala de Henares, Spain"},{"name":"Ram\u00f3n y Cajal Institute of Sanitary Research (IRYCIS), 28034 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6016-7855","authenticated-orcid":false,"given":"Cielo","family":"Garc\u00eda-Montero","sequence":"additional","affiliation":[{"name":"Department of Medicine and Medical Specialities, Faculty of Medicine and Health Sciences, University of Alcal\u00e1, Networking Research Center on for Liver and Digestive Diseases (CIBEREHD), 28801 Alcala de Henares, Spain"},{"name":"Ram\u00f3n y Cajal Institute of Sanitary Research (IRYCIS), 28034 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tatiana","family":"Pekarek","sequence":"additional","affiliation":[{"name":"Department of Medicine and Medical Specialities, Faculty of Medicine and Health Sciences, University of Alcal\u00e1, 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Sanitary Research (IRYCIS), 28034 Madrid, Spain"},{"name":"Department of Nursing and Physiotherapy, Faculty of Medicine and Health Sciences, University of Alcal\u00e1, 28801 Alcala de Henares, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7113-045X","authenticated-orcid":false,"given":"Eva Manuela","family":"Pena-Burgos","sequence":"additional","affiliation":[{"name":"Pathological Anatomy Service, University Hospital Gregorio Mara\u00f1\u00f3n, 28009 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Laura","family":"L\u00f3pez-Gonz\u00e1lez","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 Alcala de Henares, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Leonel","family":"Pekarek","sequence":"additional","affiliation":[{"name":"Department of Medicine and Medical Specialities, Faculty of Medicine and Health Sciences, University of Alcal\u00e1, Networking Research Center on for Liver and Digestive Diseases (CIBEREHD), 28801 Alcala de Henares, Spain"},{"name":"Ram\u00f3n y Cajal Institute of Sanitary Research (IRYCIS), 28034 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0412-939X","authenticated-orcid":false,"given":"Raul","family":"D\u00edaz-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 Alcala de Henares, 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