{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,19]],"date-time":"2026-10-19T15:09:01Z","timestamp":1792422541692,"version":"4.5.0"},"reference-count":44,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2022,1,14]],"date-time":"2022-01-14T00:00:00Z","timestamp":1642118400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Endothelial progenitor cells (EPCs) are involved in vascular repair and modulate properties of smooth muscle cells (SMCs) relevant for their contribution to neointima formation following injury. Considering the relevant role of the CXCL12\u2013CXCR4 axis in vascular homeostasis and the potential of EPCs and SMCs to release CXCL12 and express CXCR4, we analyzed the engagement of the CXCL12\u2013CXCR4 axis in various modes of EPC\u2013SMC interaction relevant for injury- and lipid-induced atherosclerosis. We now demonstrate that the expression and release of CXCL12 is synergistically increased in a CXCR4-dependent mechanism following EPC\u2013SMC interaction during co-cultivation or in response to recombinant CXCL12, thus establishing an amplifying feedback loop Additionally, mechanical injury of SMCs induces increased release of CXCL12, resulting in enhanced CXCR4-dependent recruitment of EPCs to SMCs. The CXCL12\u2013CXCR4 axis is crucially engaged in the EPC-triggered augmentation of SMC migration and the attenuation of SMC apoptosis but not in the EPC-mediated increase in SMC proliferation. Compared to EPCs alone, the alliance of EPC\u2013SMC is superior in promoting the CXCR4-dependent proliferation and migration of endothelial cells. When direct cell\u2013cell contact is established, EPCs protect the contractile phenotype of SMCs via CXCL12\u2013CXCR4 and reverse cholesterol-induced transdifferentiation toward a synthetic, macrophage-like phenotype. In conclusion we show that the interaction of EPCs and SMCs unleashes a CXCL12\u2013CXCR4-based autoregulatory feedback loop promoting regenerative processes and mediating SMC phenotype control to potentially guard vascular homeostasis.<\/jats:p>","DOI":"10.3390\/ijms23020867","type":"journal-article","created":{"date-parts":[[2022,1,14]],"date-time":"2022-01-14T03:14:03Z","timestamp":1642130043000},"page":"867","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Engagement of the CXCL12\u2013CXCR4 Axis in the Interaction of Endothelial Progenitor Cell and Smooth Muscle Cell to Promote Phenotype Control and Guard Vascular Homeostasis"],"prefix":"10.3390","volume":"23","author":[{"given":"Sebastian F.","family":"Mause","sequence":"first","affiliation":[{"name":"Department of Internal Medicine I, Cardiology, University Hospital Aachen, RWTH Aachen University, 52074 Aachen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisabeth","family":"Ritzel","sequence":"additional","affiliation":[{"name":"Institute for Molecular Cardiovascular Research (IMCAR), University Hospital Aachen, RWTH Aachen University, 52074 Aachen, Germany"},{"name":"Department of Otorhinolaryngology Head and Neck Surgery, Klinikum Stuttgart, 70174 Stuttgart, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annika","family":"Deck","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine I, Cardiology, University Hospital Aachen, RWTH Aachen University, 52074 Aachen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Felix","family":"Vogt","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine I, Cardiology, University Hospital Aachen, RWTH Aachen University, 52074 Aachen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1253-3272","authenticated-orcid":false,"given":"Elisa A.","family":"Liehn","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine I, Cardiology, University Hospital Aachen, RWTH Aachen University, 52074 Aachen, Germany"},{"name":"Institute of Molecular Medicine, University of South Denmark, DK-5000 Odense, Denmark"},{"name":"Victor Babes National Institute of Pathology, 050096 Bucharest, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,1,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"503","DOI":"10.1016\/S0092-8674(01)00238-0","article-title":"Atherosclerosis. the road ahead","volume":"104","author":"Glass","year":"2001","journal-title":"Cell"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1667","DOI":"10.1016\/0735-1097(90)92845-S","article-title":"Syndromes of accelerated atherosclerosis: Role of vascular injury and smooth muscle cell proliferation","volume":"15","author":"Ip","year":"1990","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"992","DOI":"10.1161\/CIRCRESAHA.120.318479","article-title":"SMC-derived hyaluronan modulates vascular SMC phenotype in murine atherosclerosis","volume":"129","author":"Hartmann","year":"2021","journal-title":"Circ. Res."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1715","DOI":"10.1161\/ATVBAHA.119.312131","article-title":"Smooth muscle cell phenotypic diversity","volume":"39","author":"Liu","year":"2019","journal-title":"Arter. Thromb. Vasc. Biol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"156","DOI":"10.1093\/cvr\/cvs115","article-title":"Smooth muscle cell phenotypic switching in atherosclerosis","volume":"95","author":"Gomez","year":"2012","journal-title":"Cardiovasc. Res."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"727","DOI":"10.1038\/s41569-019-0227-9","article-title":"Vascular smooth muscle cells in atherosclerosis","volume":"16","author":"Basatemur","year":"2019","journal-title":"Nat. Rev. Cardiol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"3013","DOI":"10.1113\/JP270033","article-title":"Origin and differentiation of vascular smooth muscle cells","volume":"593","author":"Wang","year":"2015","journal-title":"J. Physiol."},{"key":"ref_8","first-page":"212","article-title":"The CXCL12\/CXCR4 chemokine ligand\/receptor axis in cardiovascular disease","volume":"5","author":"Doring","year":"2014","journal-title":"Front. Physiol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1209","DOI":"10.1161\/ATVBAHA.113.302878","article-title":"Deficiency of endothelial CXCR4 reduces reendothelialization and enhances neointimal hyperplasia after vascular injury in atherosclerosis-prone mice","volume":"34","author":"Noels","year":"2014","journal-title":"Arter. Thromb. Vasc. Biol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1598","DOI":"10.1080\/07853890.2021.1974084","article-title":"Role and implications of the CXCL12\/CXCR4\/CXCR7 axis in atherosclerosis: Still a debate","volume":"53","author":"Murad","year":"2021","journal-title":"Ann. Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1338","DOI":"10.1161\/CIRCULATIONAHA.118.037953","article-title":"CXCL12 derived from endothelial cells promotes atherosclerosis to drive coronary artery disease","volume":"139","author":"Doring","year":"2019","journal-title":"Circulation"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"784","DOI":"10.1161\/01.RES.0000162100.52009.38","article-title":"SDF-1alpha\/CXCR4 axis is instrumental in neointimal hyperplasia and recruitment of smooth muscle progenitor cells","volume":"96","author":"Zernecke","year":"2005","journal-title":"Circ. Res."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1161\/CIRCRESAHA.107.160697","article-title":"Protective role of CXC receptor 4\/CXC ligand 12 unveils the importance of neutrophils in atherosclerosis","volume":"102","author":"Zernecke","year":"2008","journal-title":"Circ. Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"388","DOI":"10.1161\/CIRCULATIONAHA.117.027646","article-title":"Vascular CXCR4 limits atherosclerosis by maintaining arterial integrity: Evidence from mouse and human studies","volume":"136","author":"Doring","year":"2017","journal-title":"Circulation"},{"key":"ref_15","first-page":"373","article-title":"MIF and CXCL12 in Cardiovascular Diseases: Functional Differences and Similarities","volume":"6","author":"Doring","year":"2015","journal-title":"Front Immunol"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1553","DOI":"10.1016\/j.jacc.2009.10.070","article-title":"Understanding the role of endothelial progenitor cells in percutaneous coronary intervention","volume":"55","author":"Padfield","year":"2010","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"e17","DOI":"10.1161\/01.RES.0000083812.30141.74","article-title":"Intravenous transfusion of endothelial progenitor cells reduces neointima formation after vascular injury","volume":"93","author":"Werner","year":"2003","journal-title":"Circ. Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"218","DOI":"10.1016\/j.carpath.2009.04.002","article-title":"SDF-1alpha involved in mobilization and recruitment of endothelial progenitor cells after arterial injury in mice","volume":"19","author":"Yin","year":"2010","journal-title":"Cardiovasc. Pathol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"462","DOI":"10.1093\/cvr\/cvq207","article-title":"CXCR4 gene transfer contributes to in vivo reendothelialization capacity of endothelial progenitor cells","volume":"88","author":"Chen","year":"2010","journal-title":"Cardiovasc. Res."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Mause, S.F., Ritzel, E., Deck, A., Vogt, F., and Liehn, E.A. (2021). Endothelial progenitor cells modulate the phenotype of smooth muscle cells and increase their neointimal accumulation following vascular injury. Thromb. Haemost.","DOI":"10.1093\/eurheartj\/ehab724.3407"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1047","DOI":"10.1161\/CIRCRESAHA.110.226456","article-title":"Microparticles: Protagonists of a novel communication network for intercellular information exchange","volume":"107","author":"Mause","year":"2010","journal-title":"Circ. Res."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Terriaca, S., Fiorelli, E., Scioli, M.G., Fabbri, G., Storti, G., Cervelli, V., and Orlandi, A. (2021). Endothelial progenitor cell-derived extracellular vesicles: Potential therapeutic application in tissue repair and regeneration. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22126375"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"356","DOI":"10.1160\/TH11-07-0453","article-title":"The CXCR4 antagonist POL5551 is equally effective as sirolimus in reducing neointima formation without impairing re-endothelialisation","volume":"107","author":"Hamesch","year":"2012","journal-title":"Thromb. Haemost."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1608","DOI":"10.1161\/CIRCRESAHA.118.313058","article-title":"Role of resident stem cells in vessel formation and arteriosclerosis","volume":"122","author":"Zhang","year":"2018","journal-title":"Circ. Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"495","DOI":"10.1161\/CIRCULATIONAHA.109.909473","article-title":"Platelet microparticles enhance the vasoregenerative potential of angiogenic early outgrowth cells after vascular injury","volume":"122","author":"Mause","year":"2010","journal-title":"Circulation"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"599415","DOI":"10.3389\/fimmu.2020.599415","article-title":"Role of vascular smooth muscle cell plasticity and interactions in vessel wall inflammation","volume":"11","author":"Sorokin","year":"2020","journal-title":"Front. Immunol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2665","DOI":"10.1073\/pnas.0510973103","article-title":"Synergistic roles of platelet-derived growth factor-BB and interleukin-1beta in phenotypic modulation of human aortic smooth muscle cells","volume":"103","author":"Chen","year":"2006","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"13531","DOI":"10.1073\/pnas.1735526100","article-title":"Transdifferentiation of mouse aortic smooth muscle cells to a macrophage-like state after cholesterol loading","volume":"100","author":"Rong","year":"2003","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"540","DOI":"10.1093\/cvr\/cvy022","article-title":"Smooth muscle cell fate and plasticity in atherosclerosis","volume":"114","author":"Allahverdian","year":"2018","journal-title":"Cardiovasc. Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"e21260","DOI":"10.1096\/fj.202001273R","article-title":"Polyfunctionality of the CXCR4\/CXCL12 axis in health and disease: Implications for therapeutic interventions in cancer and immune-mediated diseases","volume":"35","author":"Britton","year":"2021","journal-title":"FASEB J."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"668758","DOI":"10.3389\/fimmu.2021.668758","article-title":"Pleiotropic roles of CXCR4 in wound repair and regeneration","volume":"12","author":"Chen","year":"2021","journal-title":"Front. Immunol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"858","DOI":"10.1038\/nm1075","article-title":"Progenitor cell trafficking is regulated by hypoxic gradients through HIF-1 induction of SDF-1","volume":"10","author":"Ceradini","year":"2004","journal-title":"Nat. Med."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"2491","DOI":"10.1161\/01.CIR.0000099508.76665.9A","article-title":"Crucial role of stromal cell-derived factor-1alpha in neointima formation after vascular injury in apolipoprotein E-deficient mice","volume":"108","author":"Schober","year":"2003","journal-title":"Circulation"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"ra81","DOI":"10.1126\/scisignal.2000610","article-title":"Delivery of microRNA-126 by apoptotic bodies induces CXCL12-dependent vascular protection","volume":"2","author":"Zernecke","year":"2009","journal-title":"Sci. Signal."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"734562","DOI":"10.3389\/fcvm.2021.734562","article-title":"Latest advances in endothelial progenitor cell-derived extracellular vesicles translation to the clinic","volume":"8","author":"Salybekov","year":"2021","journal-title":"Front. Cardiovasc. Med."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"717536","DOI":"10.3389\/fcvm.2021.717536","article-title":"Cardioprotective roles of endothelial progenitor cell-derived exosomes","volume":"8","author":"Zeng","year":"2021","journal-title":"Front. Cardiovasc. Med."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"436","DOI":"10.1111\/j.1365-2613.2010.00720.x","article-title":"SDF-1alpha\/CXCR4 axis is involved in glucose-potentiated proliferation and chemotaxis in rat vascular smooth muscle cells","volume":"91","author":"Jie","year":"2010","journal-title":"Int. J. Exp. Pathol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1186\/s13287-021-02185-0","article-title":"Single-cell transcriptomic profiling and characterization of endothelial progenitor cells: New approach for finding novel markers","volume":"12","author":"Abdelgawad","year":"2021","journal-title":"Stem Cell Res. Ther."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1164","DOI":"10.1161\/01.CIR.0000058702.69484.A0","article-title":"Peripheral blood \"endothelial progenitor cells\" are derived from monocyte\/macrophages and secrete angiogenic growth factors","volume":"107","author":"Rehman","year":"2003","journal-title":"Circulation"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1016\/j.imlet.2016.06.006","article-title":"CXCR4 signaling in health and disease","volume":"177","author":"Pozzobon","year":"2016","journal-title":"Immunol. Lett."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"274","DOI":"10.1160\/TH07-03-0181","article-title":"Regulation of endothelial progenitor cell homing after arterial injury","volume":"98","author":"Hristov","year":"2007","journal-title":"Thromb. Haemost."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"8270498","DOI":"10.1155\/2017\/8270498","article-title":"Progenitor cells for arterial repair: Incremental advancements towards therapeutic reality","volume":"2017","author":"Simard","year":"2017","journal-title":"Stem Cells Int."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Eslava-Alcon, S., Extremera-Garcia, M.J., Sanchez-Gomar, I., Beltran-Camacho, L., Rosal-Vela, A., Munoz, J., Ibarz, N., Alonso-Pinero, J.A., Rojas-Torres, M., and Jimenez-Palomares, M. (2020). Atherosclerotic pre-conditioning affects the paracrine role of circulating angiogenic cells ex-vivo. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21155256"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"5981","DOI":"10.1038\/s41467-020-19764-z","article-title":"Designed CXCR4 mimic acts as a soluble chemokine receptor that blocks atherogenic inflammation by agonist-specific targeting","volume":"11","author":"Kontos","year":"2020","journal-title":"Nat. Commun."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/2\/867\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,13]],"date-time":"2025-10-13T14:02:21Z","timestamp":1760364141000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/2\/867"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,1,14]]},"references-count":44,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2022,1]]}},"alternative-id":["ijms23020867"],"URL":"https:\/\/doi.org\/10.3390\/ijms23020867","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,1,14]]}}}