{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T03:32:05Z","timestamp":1789443125337,"version":"build-2803163510"},"reference-count":51,"publisher":"Oxford University Press (OUP)","issue":"11","license":[{"start":{"date-parts":[[2021,11,23]],"date-time":"2021-11-23T00:00:00Z","timestamp":1637625600000},"content-version":"vor","delay-in-days":1955,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000050","name":"National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","award":["HL-068673"],"award-info":[{"award-number":["HL-068673"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]},{"name":"T32 training","award":["HL-110853"],"award-info":[{"award-number":["HL-110853"]}]},{"DOI":"10.13039\/100000968","name":"American Heart Association Grant-In-Aid award","doi-asserted-by":"publisher","award":["14GRNT20380854"],"award-info":[{"award-number":["14GRNT20380854"]}],"id":[{"id":"10.13039\/100000968","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Wisconsin Partnership Program award","award":["ID2832"],"award-info":[{"award-number":["ID2832"]}]},{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","award":["R01EY022678"],"award-info":[{"award-number":["R01EY022678"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2016,11,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>CXCR4 is a stem\/progenitor cell surface receptor specific for the cytokine stromal cell-derived factor-1 (SDF-1\u03b1). There is evidence that bone marrow-derived CXCR4-expressing cells contribute to intimal hyperplasia (IH) by homing to the arterial subintima which is enriched with SDF-1\u03b1. We have previously found that transforming growth factor-\u03b2 (TGF\u03b2) and its signaling protein Smad3 are both upregulated following arterial injury and that TGF\u03b2\/Smad3 enhances the expression of CXCR4 in vascular smooth muscle cells (SMCs). It remains unknown, however, whether locally induced CXCR4 expression in SM22 expressing vascular SMCs plays a role in neointima formation. Here, we investigated whether elevated TGF\u03b2\/Smad3 signaling leads to the induction of CXCR4 expression locally in the injured arterial wall, thereby contributing to IH. We found prominent CXCR4 upregulation (mRNA, 60-fold; protein, 4-fold) in TGF\u03b2-treated, Smad3-expressing SMCs. Chromatin immunoprecipitation assays revealed a specific association of the transcription factor Smad3 with the CXCR4 promoter. TGF\u03b2\/Smad3 treatment also markedly enhanced SDF-1\u03b1-induced ERK1\/2 phosphorylation as well as SMC migration in a CXCR4-dependent manner. Adenoviral expression of Smad3 in balloon-injured rat carotid arteries increased local CXCR4 levels and enhanced IH, whereas SMC-specific depletion of CXCR4 in the wire-injured mouse femoral arterial wall produced a 60% reduction in IH. Our results provide the first evidence that upregulation of TGF\u03b2\/Smad3 in injured arteries induces local SMC CXCR4 expression and cell migration, and consequently IH. The Smad3\/CXCR4 pathway may provide a potential target for therapeutic interventions to prevent restenosis.<\/jats:p>","DOI":"10.1002\/stem.2442","type":"journal-article","created":{"date-parts":[[2016,6,24]],"date-time":"2016-06-24T15:36:57Z","timestamp":1466782617000},"page":"2744-2757","source":"Crossref","is-referenced-by-count":24,"title":["Local CXCR4 Upregulation in the Injured Arterial Wall Contributes to Intimal Hyperplasia"],"prefix":"10.1093","volume":"34","author":[{"given":"Xudong","family":"Shi","sequence":"first","affiliation":[{"name":"Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lian-Wang","family":"Guo","sequence":"additional","affiliation":[{"name":"Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen","family":"Seedial","sequence":"additional","affiliation":[{"name":"Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Toshio","family":"Takayama","sequence":"additional","affiliation":[{"name":"Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bowen","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengxue","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah R.","family":"Franco","sequence":"additional","affiliation":[{"name":"Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"Si","sequence":"additional","affiliation":[{"name":"Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mirnal A","family":"Chaudhary","sequence":"additional","affiliation":[{"name":"Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bo","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"K. Craig","family":"Kent","sequence":"additional","affiliation":[{"name":"Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2016,7,17]]},"reference":[{"key":"2022010901431392700_stem2442-bib-0001","doi-asserted-by":"crossref","first-page":"520","DOI":"10.1177\/0267659112452316","article-title":"Intimal hyperplasia: slow but deadly","volume":"27","author":"Mills","year":"2012","journal-title":"Perfusion"},{"key":"2022010901431392700_stem2442-bib-0002","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1016\/j.jss.2010.12.020","article-title":"TGF-\u03b2 and restenosis revisited: a smad link","volume":"167","author":"Suwanabol","year":"2011","journal-title":"J Surg Res"},{"key":"2022010901431392700_stem2442-bib-0003","doi-asserted-by":"crossref","first-page":"790","DOI":"10.1038\/nrd3810","article-title":"Targeting the TGF\u03b2 signaling pathway in disease","volume":"11","author":"Akhurst","year":"2012","journal-title":"Nat Rev Drug Discov"},{"key":"2022010901431392700_stem2442-bib-0004","doi-asserted-by":"crossref","first-page":"502","DOI":"10.1016\/j.jvs.2008.07.060","article-title":"The role of progenitor cells in the development of intimal hyperplasia","volume":"49","author":"Tsai","year":"2009","journal-title":"J Vasc Surg"},{"key":"2022010901431392700_stem2442-bib-0005","doi-asserted-by":"crossref","first-page":"1289","DOI":"10.1016\/j.jvs.2008.11.096","article-title":"Characterization of primary and restenotic atherosclerotic plaque from the superficial femoral artery: potential role of Smad3 in regulation of SMC proliferation","volume":"49","author":"Edlin","year":"2009","journal-title":"J Vasc Surg"},{"key":"2022010901431392700_stem2442-bib-0006","doi-asserted-by":"crossref","first-page":"1336","DOI":"10.1126\/science.7761852","article-title":"Inactivation of the type II TGF-beta receptor in colon cancer cells with microsatellite instability","volume":"268","author":"Markowitz","year":"1995","journal-title":"Science"},{"key":"2022010901431392700_stem2442-bib-0007","doi-asserted-by":"crossref","first-page":"326","DOI":"10.1093\/cvr\/cvp220","article-title":"Arterial gene transfer of the TGF- b signalling protein Smad3 induces adaptive remodelling following angioplasty: a role for CTGF","author":"Kundi","year":"2009","journal-title":"Cardiovasc. 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