{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T10:46:16Z","timestamp":1792665976374,"version":"4.5.0"},"reference-count":46,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2024,2,22]],"date-time":"2024-02-22T00:00:00Z","timestamp":1708560000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["ZE 526\/12-1"],"award-info":[{"award-number":["ZE 526\/12-1"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>The enzyme heme oxygenase-1 (HO-1) is pivotal in reproductive processes, particularly in placental and vascular development. This study investigated the role of HO-1 and its byproduct, carbon monoxide (CO), in trophoblastic spheroid implantation. In order to deepen our understanding of the role of HO-1 during implantation, we conducted in vivo experiments on virgin and pregnant mice, aiming to unravel the cellular and molecular mechanisms. Using siRNA, HO-1 was knocked down in JEG-3 and BeWo cells and trophoblastic spheroids were generated with or without CO treatment. Adhesion assays were performed after transferring the spheroids to RL-95 endometrial epithelial cell layers. Additionally, angiogenesis, stress, and toxicity RT2-Profiler\u2122 PCR SuperArray and PCR analyses were performed in uterine murine samples. HO-1 knockdown by siRNA impeded implantation in the 3D culture model, but this effect could be reversed by CO. Uteruses from virgin Hmox1\u2212\/\u2212 females exhibited altered expression of angiogenesis and stress markers. Furthermore, there was a distinct expression pattern of cytokines and chemokines in uteruses from gestation day 14 in Hmox1\u2212\/\u2212 females compared to Hmox1+\/+ females. This study strongly supports the essential role of HO-1 during implantation. Moreover, CO appears to have the potential to compensate for the lack of HO-1 during the spheroid attachment process. The absence of HO-1 results in dysregulation of angiogenesis and stress-related genes in the uterus, possibly contributing to implantation failure.<\/jats:p>","DOI":"10.3390\/cells13050376","type":"journal-article","created":{"date-parts":[[2024,2,22]],"date-time":"2024-02-22T03:30:26Z","timestamp":1708572626000},"page":"376","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Absence of Heme Oxygenase-1 Affects Trophoblastic Spheroid Implantation and Provokes Dysregulation of Stress and Angiogenesis Gene Expression in the Uterus"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2728-080X","authenticated-orcid":false,"given":"Maria Laura","family":"Zenclussen","sequence":"first","affiliation":[{"name":"Instituto de Salud y Ambiente del Litoral (ISAL, UNL-CONICET), Facultad de Bioqu\u00edmica y Ciencias Biol\u00f3gicas, Universidad Nacional del Litoral (UNL), Santa Fe 3000, Argentina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sina","family":"Ulrich","sequence":"additional","affiliation":[{"name":"Experimental Obstetrics and Gynecology, Medical Faculty, Otto-von-Guericke University Magdeburg, 39108 Magdeburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5752-038X","authenticated-orcid":false,"given":"Mario","family":"Bauer","sequence":"additional","affiliation":[{"name":"Department of Environmental Immunology, Helmholtz Centre for Environmental Research-UFZ, 04318 Leipzig, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beate","family":"Fink","sequence":"additional","affiliation":[{"name":"Department of Environmental Immunology, Helmholtz Centre for Environmental Research-UFZ, 04318 Leipzig, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3544-4552","authenticated-orcid":false,"given":"Ana Claudia","family":"Zenclussen","sequence":"additional","affiliation":[{"name":"Experimental Obstetrics and Gynecology, Medical Faculty, Otto-von-Guericke University Magdeburg, 39108 Magdeburg, Germany"},{"name":"Department of Environmental Immunology, Helmholtz Centre for Environmental Research-UFZ, 04318 Leipzig, Germany"},{"name":"Perinatal Immunology, Saxonian Incubator for Clinical Translation (SIKT), Medical Faculty, Leipzig University, 04103 Leipzig, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6427-3724","authenticated-orcid":false,"given":"Anne","family":"Schumacher","sequence":"additional","affiliation":[{"name":"Experimental Obstetrics and Gynecology, Medical Faculty, Otto-von-Guericke University Magdeburg, 39108 Magdeburg, Germany"},{"name":"Department of Environmental Immunology, Helmholtz Centre for Environmental Research-UFZ, 04318 Leipzig, Germany"},{"name":"Perinatal Immunology, Saxonian Incubator for Clinical Translation (SIKT), Medical Faculty, Leipzig University, 04103 Leipzig, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7990-2175","authenticated-orcid":false,"given":"Nicole","family":"Meyer","sequence":"additional","affiliation":[{"name":"Experimental Obstetrics and Gynecology, Medical Faculty, Otto-von-Guericke University Magdeburg, 39108 Magdeburg, Germany"},{"name":"Department of Environmental Immunology, Helmholtz Centre for Environmental Research-UFZ, 04318 Leipzig, Germany"},{"name":"Perinatal Immunology, Saxonian Incubator for Clinical Translation (SIKT), Medical Faculty, Leipzig University, 04103 Leipzig, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,2,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"513","DOI":"10.1006\/geno.1994.1213","article-title":"Chromosomal Localization of the Human Heme Oxygenase Genes: Heme Oxygenase-1 (HMOX1) Maps to Chromosome 22q12 and Heme Oxygenase-2 (HMOX2) Maps to Chromosome 16p13.3","volume":"20","author":"Kutty","year":"1994","journal-title":"Genomics"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Ryter, S.W. 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