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The chemokine ligand-12 (CXCL12) and its receptor chemokine receptor 4 (CXCR4) are expressed at the fetal\u2013maternal interface and implicated in trophoblast migration, immune regulation, and angiogenesis, but their in vivo role in early placental functional development remains unclear. The objective of this study was to determine whether suppression of CXCL12\/CXCR4 signaling during implantation alters placental programming in sheep. Ewes received intrauterine infusion of CXCR4 antagonist plerixafor (AMD3100) from Day 12\u201319 of pregnancy, and tissues were collected on Day 20. Pregnancy rates were not affected by treatment; however, pregnancy-associated glycoprotein abundance was increased in treated ewes, indicating altered trophoblast differentiation. Inhibiting CXCR4 reduced expression of angiogenic factors including vascular endothelial growth factor A, placental growth factor, fms-like tyrosine kinase-1, and angiopoietin-1 in endometrium, consistent with impaired vascular development. Suppression of CXCR4 also shifted immune signaling toward a pro-inflammatory profile, with increased interferon-gamma and interleukin-12 and decreased transforming growth factor beta. In addition, expression of glucose and amino acid solute carrier family (SLC) transporters, including SLC2A1, SLC2A3, SLC38, and SLC7 family members, was altered in fetal membranes and endometrium, accompanied by increased autophagy marker LC3B-phosphatidylethanolamine conjugate (LC3B-II), suggesting metabolic stress. These findings demonstrate that CXCL12\/CXCR4 signaling is not required for conceptus attachment but is important for coordinated development of vascular, immune, and metabolic pathways during early placentation. Disruption of this axis produces molecular changes consistent with placental insufficiency, supporting a central role for CXCL12\/CXCR4 in establishing functional placental capacity.<\/jats:p>","DOI":"10.1093\/biolre\/ioag211","type":"journal-article","created":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T15:46:01Z","timestamp":1790264761000},"source":"Crossref","is-referenced-by-count":0,"title":["CXCL12\/CXCR4 signaling coordinates trophoblast, immune, vascular, and metabolic programming during early placentation in sheep"],"prefix":"10.1093","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1936-6048","authenticated-orcid":false,"given":"Ryan","family":"Ashley","sequence":"first","affiliation":[{"name":"Department of Animal and Range Sciences, New Mexico State University , Las Cruces, NM, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Makayla","family":"Mullins","sequence":"additional","affiliation":[{"name":"Department of Animal and Range Sciences, New 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