{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T14:56:00Z","timestamp":1791644160081,"version":"4.3.4"},"reference-count":62,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,8,16]],"date-time":"2021-08-16T00:00:00Z","timestamp":1629072000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Vet. Sci."],"abstract":"<jats:p>The placenta, a unique organ that only develops during pregnancy, is essential for nutrient, oxygen, and waste exchange between offspring and mother. Yet, despite its importance, the placenta remains one of the least understood organs and knowledge of early placental formation is particularly limited. Abnormalities in placental development result in placental dysfunction or insufficiency whereby normal placental physiology is impaired. Placental dysfunction is a frequent source of pregnancy loss in livestock, inflicting serious economic impact to producers. Though the underlying causes of placental dysfunction are not well-characterized, initiation of disease is thought to occur during establishment of functional fetal and placental circulation. A comprehensive understanding of the mechanisms controlling placental growth and vascularization is necessary to improve reproductive success in livestock. We propose chemokine C-X-C motif ligand 12 (CXCL12) signaling through its receptor CXCR4 functions as a chief coordinator of vascularization through direct actions on fetal trophoblast and maternal endometrial and immune cells. To investigate CXCL12\u2013CXCR4 signaling on uteroplacental vascular remodeling at the fetal\u2013maternal interface, we utilized a CXCR4 antagonist (AMD3100). On day 12 post-breeding in sheep, osmotic pumps were surgically installed and delivered either AMD3100 or saline into the uterine lumen ipsilateral to the corpus luteum for 14 days. On day 35 of ovine pregnancy, fetal\/placental and endometrial tissues were collected, snap-frozen in liquid nitrogen, and uterine horn cross sections were preserved for immunofluorescent analysis. Suppressing CXCL12\u2013CXCR4 at the fetal\u2013maternal interface during initial placental vascularization resulted in diminished abundance of select angiogenic factors in fetal and maternal placenta on day 35. Compared to control, less vascular endothelial growth factor (VEGF) and VEFG receptor 2 (KDR) were observed in endometrium when CXCL12\u2013CXCR4 was diminished. Less VEGF was also evident in fetal placenta (cotyledons) in ewes receiving AMD3100 infusion compared to control. Suppressing CXCL12\u2013CXCR4 at the fetal\u2013maternal interface also resulted in greater autophagy induction in fetal and maternal placenta compared to control, suggestive of CXCL12\u2013CXCR4 impacting cell survival. CXCL12\u2013CXCR4 signaling may govern placental homeostasis by serving as a critical upstream mediator of vascularization and cell viability, thereby ensuring appropriate placental development.<\/jats:p>","DOI":"10.3389\/fvets.2021.650687","type":"journal-article","created":{"date-parts":[[2021,8,16]],"date-time":"2021-08-16T09:34:31Z","timestamp":1629106471000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":17,"title":["Inhibition of the C-X-C Motif Chemokine 12 (CXCL12) and Its Receptor CXCR4 Reduces Utero-Placental Expression of the VEGF System and Increases Utero-Placental Autophagy"],"prefix":"10.3389","volume":"8","author":[{"given":"Ryan L.","family":"Ashley","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cheyenne L.","family":"Runyan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marlie M.","family":"Maestas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisa","family":"Trigo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gail","family":"Silver","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,8,16]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1004","DOI":"10.1095\/biolreprod.104.037234","article-title":"Influence of maternal nutrition on messenger RNA expression of placental angiogenic factors and their receptors at midgestation in adolescent sheep","volume":"72","author":"Redmer","year":"2005","journal-title":"Biol Reprod."},{"key":"B2","doi-asserted-by":"publisher","first-page":"151","DOI":"10.1046\/j.1365-2613.2002.00277.x","article-title":"Angiogenesis in the female reproductive organs: pathological implications","volume":"83","author":"Reynolds","year":"2002","journal-title":"Int J Exp Pathol."},{"key":"B3","doi-asserted-by":"publisher","first-page":"797","DOI":"10.1136\/adc.68.6.797","article-title":"Fetal and infant origins of cardiovascular disease","volume":"68","author":"Barker","year":"1993","journal-title":"Arch Dis Child."},{"key":"B4","doi-asserted-by":"publisher","first-page":"62","DOI":"10.1007\/BF00399095","article-title":"Type 2 (non-insulin-dependent) diabetes mellitus, hypertension and hyperlipidaemia (syndrome X): relation to reduced fetal growth","volume":"36","author":"Barker","year":"1993","journal-title":"Diabetologia."},{"key":"B5","first-page":"2","article-title":"Classification of intrauterine growth retardation","volume":"12","author":"Brar","year":"1988","journal-title":"Semin Perinatol."},{"key":"B6","doi-asserted-by":"publisher","first-page":"376","DOI":"10.1097\/00006254-199606000-00023","article-title":"Idiopathic fetal growth restriction: a pathophysiologic approach","volume":"51","author":"Ghidini","year":"1996","journal-title":"Obstet Gynecol Surv."},{"key":"B7","doi-asserted-by":"publisher","first-page":"1019","DOI":"10.1136\/bmj.303.6809.1019","article-title":"Fetal and infant growth and impaired glucose tolerance at age 64","volume":"303","author":"Hales","year":"1991","journal-title":"BMJ."},{"key":"B8","doi-asserted-by":"publisher","first-page":"99","DOI":"10.1097\/00003081-199203000-00015","article-title":"Intrauterine growth retardation: definition, classification, and etiology","volume":"35","author":"Pollack","year":"1992","journal-title":"Clin Obstet Gynecol."},{"key":"B9","doi-asserted-by":"publisher","first-page":"2316","DOI":"10.2527\/jas.2006-156","article-title":"Board-invited review: intrauterine growth retardation: implications for the animal sciences","volume":"84","author":"Wu","year":"2006","journal-title":"J Anim Sci."},{"key":"B10","doi-asserted-by":"publisher","first-page":"288","DOI":"10.1016\/j.theriogenology.2016.04.042","article-title":"Maternal environment and placental vascularization in small ruminants","volume":"86","author":"Bairagi","year":"2016","journal-title":"Theriogenology."},{"key":"B11","doi-asserted-by":"publisher","first-page":"4530","DOI":"10.3390\/ijms20184530","article-title":"Immunohistochemical examination of trophoblast syncytialization during early placentation in sheep","volume":"20","author":"Seo","year":"2019","journal-title":"Int J Mol Sci"},{"key":"B12","doi-asserted-by":"publisher","first-page":"663","DOI":"10.1093\/abbs\/gmv064","article-title":"Insights into the mechanism of CXCL12-mediated signaling in trophoblast functions and placental angiogenesis","volume":"47","author":"Wang","year":"2015","journal-title":"Acta Biochim Biophys Sin (Shanghai)."},{"key":"B13","doi-asserted-by":"publisher","first-page":"468","DOI":"10.1093\/biolre\/ioaa203","article-title":"CXCR4 signaling at the fetal-maternal interface may drive inflammation and syncytia formation during ovine pregnancydagger","volume":"104","author":"McIntosh","year":"2021","journal-title":"Biol Reprod."},{"key":"B14","doi-asserted-by":"publisher","first-page":"e13181","DOI":"10.1111\/aji.13181","article-title":"Intrauterine inhibition of chemokine receptor 4 signaling modulates local and systemic inflammation in ovine pregnancy","volume":"82","author":"McIntosh","year":"2019","journal-title":"Am J Reprod Immunol."},{"key":"B15","doi-asserted-by":"publisher","first-page":"1144","DOI":"10.2527\/jas2016.1271","article-title":"Inhibition of chemokine (C-X-C motif) receptor four (CXCR4) at the fetal-maternal interface during early gestation in sheep: alterations in expression of chemokines, angiogenic factors and their receptors","volume":"95","author":"Quinn","year":"2017","journal-title":"J Anim Sci."},{"key":"B16","doi-asserted-by":"publisher","first-page":"102","DOI":"10.1093\/biolre\/ioz073","article-title":"CXCR4 signaling at the ovine fetal-maternal interface regulates vascularization, CD34+ cell presence, and autophagy in the endometrium","volume":"101","author":"Runyan","year":"2019","journal-title":"Biol Reprod."},{"key":"B17","doi-asserted-by":"publisher","first-page":"165","DOI":"10.1530\/REP-09-0548","article-title":"Placental development during early pregnancy in sheep: vascular growth and expression of angiogenic factors in maternal placenta","volume":"140","author":"Grazul-Bilska","year":"2010","journal-title":"Reproduction."},{"key":"B18","doi-asserted-by":"publisher","first-page":"529","DOI":"10.1530\/REP-10-0505","article-title":"Placental development during early pregnancy in sheep: cell proliferation, global methylation and angiogenesis in the fetal placenta","volume":"141","author":"Grazul-Bilska","year":"2011","journal-title":"Reproduction."},{"key":"B19","doi-asserted-by":"publisher","first-page":"698","DOI":"10.1095\/biolreprod47.5.698","article-title":"Growth and microvascular development of the uterus during early pregnancy in ewes","volume":"47","author":"Reynolds","year":"1992","journal-title":"Biol Reprod."},{"key":"B20","doi-asserted-by":"publisher","first-page":"1667","DOI":"10.1128\/AAC.44.6.1667-1673.2000","article-title":"Pharmacokinetics and safety of AMD-3100, a novel antagonist of the CXCR-4 chemokine receptor, in human volunteers","volume":"44","author":"Hendrix","year":"2000","journal-title":"Antimicrob Agents Chemother."},{"key":"B21","doi-asserted-by":"publisher","first-page":"337","DOI":"10.1677\/JOE-07-0123","article-title":"Maternal betamethasone administration reduces binucleate cell number and placental lactogen in sheep","volume":"194","author":"Braun","year":"2007","journal-title":"J Endocrinol."},{"key":"B22","doi-asserted-by":"publisher","first-page":"260","DOI":"10.1111\/j.1439-0531.2008.01171.x","article-title":"Embryonic and early foetal losses in cattle and other ruminants","volume":"43","author":"Diskin","year":"2008","journal-title":"Reprod Domest Anim."},{"key":"B23","doi-asserted-by":"publisher","first-page":"297","DOI":"10.1016\/j.anireprosci.2006.08.008","article-title":"Embryo survival in dairy cows managed under pastoral conditions","volume":"96","author":"Diskin","year":"2006","journal-title":"Anim Reprod Sci."},{"key":"B24","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1071\/RD03073","article-title":"Towards an embryocentric world: the current and potential uses of embryo technologies in dairy production","volume":"16","author":"Hansen","year":"2004","journal-title":"Reprod Fertil Dev."},{"key":"B25","doi-asserted-by":"publisher","first-page":"513","DOI":"10.1016\/j.anireprosci.2004.04.015","article-title":"The effect of embryonic death rates in cattle on the efficacy of estrus synchronization programs","volume":"83","author":"Santos","year":"2004","journal-title":"Anim Reprod Sci"},{"key":"B26","doi-asserted-by":"publisher","first-page":"250","DOI":"10.1016\/j.theriogenology.2009.09.005","article-title":"Embryo loss in cattle between days 7 and 16 of pregnancy","volume":"73","author":"Berg","year":"2010","journal-title":"Theriogenology."},{"key":"B27","doi-asserted-by":"publisher","first-page":"463","DOI":"10.1530\/jrf.0.0590463","article-title":"Fertilization and embryonic mortality rates in beef heifers after artificial insemination","volume":"59","author":"Diskin","year":"1980","journal-title":"J Reprod Fertil."},{"key":"B28","doi-asserted-by":"publisher","first-page":"401","DOI":"10.1136\/vr.109.18.401","article-title":"Reproductive wastage following artificial insemination of heifers","volume":"109","author":"Roche","year":"1981","journal-title":"Vet Rec."},{"key":"B29","doi-asserted-by":"publisher","first-page":"244","DOI":"10.1071\/RD11914","article-title":"Embryo death in cattle: an update","volume":"24","author":"Diskin","year":"2011","journal-title":"Reprod Fertil Dev."},{"key":"B30","doi-asserted-by":"publisher","first-page":"239","DOI":"10.1016\/j.anireprosci.2003.12.012","article-title":"Factors affecting conception rate after artificial insemination and pregnancy loss in lactating dairy cows","volume":"84","author":"Chebel","year":"2004","journal-title":"Anim Reprod Sci."},{"key":"B31","doi-asserted-by":"publisher","first-page":"355","DOI":"10.1387\/ijdb.082799lr","article-title":"Uteroplacental vascular development and placental function: an update","volume":"54","author":"Reynolds","year":"2010","journal-title":"Int J Dev Biol."},{"key":"B32","doi-asserted-by":"publisher","first-page":"689","DOI":"10.1016\/j.placenta.2004.11.010","article-title":"Animal models of placental angiogenesis","volume":"26","author":"Reynolds","year":"2005","journal-title":"Placenta."},{"key":"B33","doi-asserted-by":"publisher","first-page":"51","DOI":"10.1113\/jphysiol.2005.104430","article-title":"Evidence for altered placental blood flow and vascularity in compromised pregnancies","volume":"572","author":"Reynolds","year":"2006","journal-title":"J Physiol"},{"key":"B34","doi-asserted-by":"publisher","first-page":"103","DOI":"10.1016\/j.placenta.2003.10.004","article-title":"Aspects of human fetoplacental vasculogenesis and angiogenesis","volume":"25","author":"Charnock-Jones","year":"2004","journal-title":"I Mol Regul Placenta."},{"key":"B35","doi-asserted-by":"publisher","first-page":"114","DOI":"10.1016\/j.placenta.2003.10.009","article-title":"Aspects of human fetoplacental vasculogenesis and angiogenesis","volume":"25","author":"Kaufmann","year":"2004","journal-title":"II Changes During Normal Preg Placenta."},{"key":"B36","volume-title":"Maternal Cardiovascular and Other Physiological Responses to the Endocrinology of Pregnancy","author":"Magness","year":"1998"},{"key":"B37","doi-asserted-by":"publisher","first-page":"829","DOI":"10.1016\/j.placenta.2004.04.011","article-title":"Morphometric evidence that villous development and fetoplacental angiogenesis are compromised by intrauterine growth restriction but not by pre-eclampsia","volume":"25","author":"Mayhew","year":"2004","journal-title":"Placenta."},{"key":"B38","doi-asserted-by":"publisher","first-page":"886","DOI":"10.1096\/fasebj.6.3.1371260","article-title":"Angiogenesis in the female reproductive system","volume":"6","author":"Reynolds","year":"1992","journal-title":"FASEB J."},{"key":"B39","doi-asserted-by":"publisher","first-page":"1839","DOI":"10.2527\/1995.7361839x","article-title":"Utero-placental vascular development and placental function","volume":"73","author":"Reynolds","year":"1995","journal-title":"J Anim Sci."},{"key":"B40","doi-asserted-by":"publisher","first-page":"E61","DOI":"10.2527\/jas.2009-2359","article-title":"Developmental programming: the concept, large animal models, and the key role of uteroplacental vascular development","volume":"88","author":"Reynolds","year":"2010","journal-title":"J Anim Sci"},{"key":"B41","doi-asserted-by":"publisher","first-page":"43","DOI":"10.1113\/jphysiol.2004.081745","article-title":"Placental angiogenesis in sheep models of compromised pregnancy","volume":"565","author":"Reynolds","year":"2005","journal-title":"J Physiol"},{"key":"B42","doi-asserted-by":"publisher","first-page":"105","DOI":"10.1530\/ror.0.0020105","article-title":"Fetal undernutrition and disease in later life","volume":"2","author":"Barker","year":"1997","journal-title":"Rev Reprod."},{"key":"B43","doi-asserted-by":"publisher","first-page":"73","DOI":"10.1016\/S0303-7207(01)00634-7","article-title":"Fetal programming of appetite and obesity","volume":"185","author":"Breier","year":"2001","journal-title":"Mol Cell Endocrinol."},{"key":"B44","doi-asserted-by":"publisher","first-page":"587","DOI":"10.1016\/S0049-3848(00)00292-9","article-title":"SDF-1 activity on microvascular endothelial cells: consequences on angiogenesis in in vitro and in vivo models","volume":"99","author":"Mirshahi","year":"2000","journal-title":"Thromb Res."},{"key":"B45","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1016\/j.domaniend.2013.12.004","article-title":"Activation of the CXCL12\/CXCR4 signaling axis may drive vascularization of the ovine placenta","volume":"47","author":"Quinn","year":"2014","journal-title":"Domest Anim Endocrinol."},{"key":"B46","doi-asserted-by":"publisher","first-page":"359","DOI":"10.1080\/mic.10.3-4.359.370","article-title":"Role of chemokines in angiogenesis: CXCL12\/SDF-1 and CXCR4 interaction, a key regulator of endothelial cell responses","volume":"10","author":"Salcedo","year":"2003","journal-title":"Microcirculation."},{"key":"B47","doi-asserted-by":"publisher","first-page":"1125","DOI":"10.1016\/S0002-9440(10)65365-5","article-title":"Vascular endothelial growth factor and basic fibroblast growth factor induce expression of CXCR4 on human endothelial cells: In vivo neovascularization induced by stromal-derived factor-1alpha","volume":"154","author":"Salcedo","year":"1999","journal-title":"Am J Pathol."},{"key":"B48","doi-asserted-by":"publisher","first-page":"148","DOI":"10.1186\/1477-7827-9-148","article-title":"The chemokine receptor CXCR4 and its ligand CXCL12 are activated during implantation and placentation in sheep","volume":"9","author":"Ashley","year":"2011","journal-title":"Reprod Biol Endocrinol."},{"key":"B49","doi-asserted-by":"publisher","first-page":"577","DOI":"10.1016\/j.placenta.2006.08.003","article-title":"Placental abnormalities in ovine somatic cell clones at term: a light and electron microscopic investigation","volume":"28","author":"Palmieri","year":"2007","journal-title":"Placenta."},{"key":"B50","doi-asserted-by":"publisher","first-page":"e2013060","DOI":"10.4084\/mjhid.2013.060","article-title":"Von Willebrand factor, angiodysplasia and angiogenesis","volume":"5","author":"Randi","year":"2013","journal-title":"Mediterr J Hematol Infect Dis."},{"key":"B51","doi-asserted-by":"publisher","first-page":"2737","DOI":"10.1172\/JCI107469","article-title":"Antihemophilic factor antigen Localization in endothelial cells by immunofluorescent microscopy","volume":"52","author":"Hoyer","year":"1973","journal-title":"J Clin Invest."},{"key":"B52","doi-asserted-by":"publisher","first-page":"7194","DOI":"10.1038\/sj.onc.1210535","article-title":"The VEGF angiogenic switch of fibroblasts is regulated by MMP-7 from cancer cells","volume":"26","author":"Ito","year":"2007","journal-title":"Oncogene."},{"key":"B53","doi-asserted-by":"publisher","first-page":"2474","DOI":"10.1016\/S0959-8049(96)00379-6","article-title":"Quantification of angiogenesis in solid human tumours: an international consensus on the methodology and criteria of evaluation","author":"Vermeulen","year":"1996","journal-title":"Eur J Cancer"},{"key":"B54","doi-asserted-by":"publisher","first-page":"281","DOI":"10.1002\/(SICI)1097-0215(20000115)85:2%3C281::AID-IJC21%3E3.0.CO;2-3","article-title":"Expression of Von Willebrand factor, an endothelial cell marker, is up-regulated by angiogenesis factors: a potential method for objective assessment of tumor angiogenesis","volume":"85","author":"Zanetta","year":"2000","journal-title":"Int J Cancer."},{"key":"B55","doi-asserted-by":"publisher","first-page":"70","DOI":"10.1016\/j.tcb.2003.12.002","article-title":"Autophagy: in sickness and in health","volume":"14","author":"Cuervo","year":"2004","journal-title":"Trends Cell Biol."},{"key":"B56","doi-asserted-by":"publisher","first-page":"463","DOI":"10.1016\/S1534-5807(04)00099-1","article-title":"Development by self-digestion: molecular mechanisms and biological functions of autophagy","volume":"6","author":"Levine","year":"2004","journal-title":"Dev Cell."},{"key":"B57","doi-asserted-by":"publisher","first-page":"2861","DOI":"10.1101\/gad.1599207","article-title":"Autophagy: process and function","volume":"21","author":"Mizushima","year":"2007","journal-title":"Genes Dev."},{"key":"B58","doi-asserted-by":"publisher","first-page":"453","DOI":"10.1016\/j.bbrc.2003.07.023","article-title":"Autophagy: a regulated bulk degradation process inside cells","volume":"313","author":"Yoshimori","year":"2004","journal-title":"Biochem Biophys Res Commun."},{"key":"B59","doi-asserted-by":"publisher","first-page":"97","DOI":"10.5653\/cerm.2014.41.3.97","article-title":"The role of autophagy in the placenta as a regulator of cell death","volume":"41","author":"Gong","year":"2014","journal-title":"Clin Exp Reprod Med."},{"key":"B60","doi-asserted-by":"publisher","first-page":"e0157594","DOI":"10.1371\/journal.pone.0157594","article-title":"Evidence of placental autophagy during early pregnancy after transfer of in vitro produced (IVP) sheep embryos","volume":"11","author":"Toschi","year":"2016","journal-title":"PLoS ONE."},{"key":"B61","doi-asserted-by":"publisher","first-page":"R128","DOI":"10.1186\/bcr3074","article-title":"Opposing roles of CXCR4 and CXCR7 in breast cancer metastasis","volume":"13","author":"Hernandez","year":"2011","journal-title":"Breast Cancer Res."},{"key":"B62","doi-asserted-by":"publisher","first-page":"R54","DOI":"10.1186\/bcr3665","article-title":"C-X-C motif chemokine 12\/C-X-C chemokine receptor type 7 signaling regulates breast cancer growth and metastasis by modulating the tumor microenvironment","volume":"16","author":"Wani","year":"2014","journal-title":"Breast Cancer Res."}],"container-title":["Frontiers in Veterinary Science"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fvets.2021.650687\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,8,16]],"date-time":"2021-08-16T09:34:35Z","timestamp":1629106475000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fvets.2021.650687\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,8,16]]},"references-count":62,"alternative-id":["10.3389\/fvets.2021.650687"],"URL":"https:\/\/doi.org\/10.3389\/fvets.2021.650687","relation":{},"ISSN":["2297-1769"],"issn-type":[{"value":"2297-1769","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,8,16]]},"article-number":"650687"}}