{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T04:42:09Z","timestamp":1791088929271,"version":"4.1.0"},"reference-count":47,"publisher":"MDPI AG","issue":"24","license":[{"start":{"date-parts":[[2025,12,16]],"date-time":"2025-12-16T00:00:00Z","timestamp":1765843200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["R01-DK132888"],"award-info":[{"award-number":["R01-DK132888"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["R01-DK136297"],"award-info":[{"award-number":["R01-DK136297"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["R01-DK144860"],"award-info":[{"award-number":["R01-DK144860"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["F32-HL158216"],"award-info":[{"award-number":["F32-HL158216"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000738","name":"Department of Veterans Affairs","doi-asserted-by":"publisher","award":["IK6-BX006823"],"award-info":[{"award-number":["IK6-BX006823"]}],"id":[{"id":"10.13039\/100000738","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000738","name":"Department of Veterans Affairs","doi-asserted-by":"publisher","award":["I01-BX006080"],"award-info":[{"award-number":["I01-BX006080"]}],"id":[{"id":"10.13039\/100000738","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>The mouse carotid\u2013jugular arteriovenous fistula (AVF) is a widely adopted surgical model to study venous remodeling after AVF creation. Despite its increasing use, the extent to which this model recapitulates the cellular and molecular remodeling processes observed in humans remains uncertain, which is essential for validating its translational relevance. Using bulk and single-cell RNA sequencing, we have depicted the transcriptional and cellular evolution of the mouse jugular vein after AVF anastomosis. Global transcriptomic profiling revealed that venous remodeling begins with a robust inflammatory response, followed by a prominent extracellular matrix (ECM) remodeling phase that peaks at postoperative day 10. Single-cell analyses confirmed the role of macrophage (3-fold) and neutrophil infiltration (12-fold) in sustaining the onset of venous remodeling. These monocytes\/macrophages exhibited marked upregulation of pro-inflammatory and pro-fibrotic genes, including Il1b, Spp1, Fn1, Thbs1, and Tgfb1. Evidence of the differentiation of fibroblasts into myofibroblasts positive for Postn, Col8a1, and Thbs1 emerged by postoperative day 5. The temporal dynamics of differentially expressed genes in these myofibroblasts closely mirrored the ECM gene expression patterns identified by bulk RNA-seq, indicating that they are the principal source of ECM deposition in the AVF. Cell-to-cell communication analyses highlighted macrophages and fibroblasts as the main populations driving postoperative remodeling. Comparative analysis with single-cell data from human pre-access veins and AVFs demonstrated that the mouse model reproduces the core inflammatory\u2013fibrotic axis of fibroblast activation observed in humans, supporting its utility for mechanistic studies of postoperative ECM remodeling.<\/jats:p>","DOI":"10.3390\/cells14241998","type":"journal-article","created":{"date-parts":[[2025,12,16]],"date-time":"2025-12-16T09:57:24Z","timestamp":1765879044000},"page":"1998","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Sequential Inflammatory and Matrisome Programs Drive Remodeling of the Mouse Carotid\u2013Jugular Arteriovenous Fistula"],"prefix":"10.3390","volume":"14","author":[{"given":"Filipe F.","family":"Stoyell-Conti","sequence":"first","affiliation":[{"name":"DeWitt Daughtry Family Department of Surgery, Leonard M. Miller School of Medicine, University of Miami, Miami, FL 33136, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander M.","family":"Kaiser","sequence":"additional","affiliation":[{"name":"DeWitt Daughtry Family Department of Surgery, Leonard M. Miller School of Medicine, University of Miami, Miami, FL 33136, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miguel G.","family":"Rojas","sequence":"additional","affiliation":[{"name":"DeWitt Daughtry Family Department of Surgery, Leonard M. Miller School of Medicine, University of Miami, Miami, FL 33136, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuntao","family":"Wei","sequence":"additional","affiliation":[{"name":"DeWitt Daughtry Family Department of Surgery, Leonard M. Miller School of Medicine, University of Miami, Miami, FL 33136, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew S.","family":"Sussman","sequence":"additional","affiliation":[{"name":"DeWitt Daughtry Family Department of Surgery, Leonard M. Miller School of Medicine, University of Miami, Miami, FL 33136, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1987-5555","authenticated-orcid":false,"given":"Juan S.","family":"Lopez-McCormick","sequence":"additional","affiliation":[{"name":"DeWitt Daughtry Family Department of Surgery, Leonard M. Miller School of Medicine, University of Miami, Miami, FL 33136, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marwan","family":"Tabbara","sequence":"additional","affiliation":[{"name":"DeWitt Daughtry Family Department of Surgery, Leonard M. Miller School of Medicine, University of Miami, Miami, FL 33136, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaofeng","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Sciences, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9370-276X","authenticated-orcid":false,"given":"Roberto I.","family":"Vazquez-Padron","sequence":"additional","affiliation":[{"name":"DeWitt Daughtry Family Department of Surgery, Leonard M. Miller School of Medicine, University of Miami, Miami, FL 33136, USA"},{"name":"Research Service, Bruce W. Carter Veterans Affairs Medical Center, Miami, FL 33125, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3009-8761","authenticated-orcid":false,"given":"Laisel","family":"Martinez","sequence":"additional","affiliation":[{"name":"DeWitt Daughtry Family Department of Surgery, Leonard M. Miller School of Medicine, University of Miami, Miami, FL 33136, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,12,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1166","DOI":"10.1016\/j.jvs.2018.01.049","article-title":"Utilization, patency, and complications associated with vascular access for hemodialysis in the United States","volume":"68","author":"Arhuidese","year":"2018","journal-title":"J. Vasc. Surg."},{"key":"ref_2","first-page":"e53294","article-title":"A novel murine model of arteriovenous fistula failure: The surgical procedure in detail","volume":"108","author":"Wong","year":"2016","journal-title":"J. Vis. Exp."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"H1718","DOI":"10.1152\/ajpheart.00590.2013","article-title":"The mouse aortocaval fistula recapitulates human arteriovenous fistula maturation","volume":"305","author":"Yamamoto","year":"2013","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1177\/11297298211026083","article-title":"Cardiac changes following arteriovenous fistula creation in a mouse model","volume":"24","author":"Ingle","year":"2023","journal-title":"J. Vasc. Access"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2509","DOI":"10.1161\/ATVBAHA.124.320933","article-title":"Endothelial TGF-beta signaling regulates endothelial-mesenchymal transition during arteriovenous fistula remodeling in mice with chronic kidney disease","volume":"44","author":"Zhang","year":"2024","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"22786","DOI":"10.1038\/s41598-023-49573-5","article-title":"Effects of endothelial nitric oxide synthase on mouse arteriovenous fistula hemodynamics","volume":"13","author":"Baltazar","year":"2023","journal-title":"Sci. Rep."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"100392","DOI":"10.1016\/j.jvssci.2025.100392","article-title":"Sox17 mediates venous adaptive remodeling after arteriovenous fistula creation","volume":"6","author":"Aoyagi","year":"2025","journal-title":"JVS Vasc. Sci."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"101816","DOI":"10.1016\/j.jbc.2022.101816","article-title":"Downregulation of the endothelial histone demethylase JMJD3 is associated with neointimal hyperplasia of arteriovenous fistulas in kidney failure","volume":"298","author":"Feng","year":"2022","journal-title":"J. Biol. Chem."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1630","DOI":"10.1681\/ASN.2020101458","article-title":"Anti human CX3CR1 VHH molecule attenuates venous neointimal hyperplasia of arteriovenous fistula in mouse model","volume":"32","author":"Misra","year":"2021","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Martinez, L., Stoyell-Conti, F.F., Tabbara, M., Rojas, M.G., Pereira-Simon, S., Falcon, N.S., Lopez, R.H., Galtes, D., Kosanovic, C., and Griswold, A.J. (2025). The single-cell landscape of the human vein after arteriovenous fistula creation and implications for maturation failure. Kidney Int., in press.","DOI":"10.1016\/j.kint.2025.08.024"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"320","DOI":"10.1038\/s41684-020-00659-x","article-title":"Experimental murine arteriovenous fistula model to study restenosis after transluminal angioplasty","volume":"49","author":"Cai","year":"2020","journal-title":"Lab Anim."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"837","DOI":"10.1016\/j.ekir.2023.01.008","article-title":"The Transcriptomics of the Human Vein Transformation After Arteriovenous Fistula Anastomosis Uncovers Layer-Specific Remodeling and Hallmarks of Maturation Failure","volume":"8","author":"Martinez","year":"2023","journal-title":"Kidney Int. Rep."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1523","DOI":"10.1038\/s41467-019-09234-6","article-title":"Metascape provides a biologist-oriented resource for the analysis of systems-level datasets","volume":"10","author":"Zhou","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"D1136","DOI":"10.1093\/nar\/gkz849","article-title":"MatrisomeDB: The ECM-protein knowledge database","volume":"48","author":"Shao","year":"2020","journal-title":"Nucleic Acids Res."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"118582","DOI":"10.1016\/j.atherosclerosis.2024.118582","article-title":"Gene inactivation of lysyl oxidase in smooth muscle cells reduces atherosclerosis burden and plaque calcification in hyperlipidemic mice","volume":"397","author":"Zigmond","year":"2024","journal-title":"Atherosclerosis"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1677","DOI":"10.1038\/s41592-025-02748-6","article-title":"GeneAgent: Self-verification language agent for gene-set analysis using domain databases","volume":"22","author":"Wang","year":"2025","journal-title":"Nat. Methods"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1016\/j.cels.2015.12.004","article-title":"The Molecular Signatures Database (MSigDB) hallmark gene set collection","volume":"1","author":"Liberzon","year":"2015","journal-title":"Cell Syst."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1088","DOI":"10.1038\/s41467-021-21246-9","article-title":"Inference and analysis of cell-cell communication using CellChat","volume":"12","author":"Jin","year":"2021","journal-title":"Nat. Commun."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"496","DOI":"10.1038\/s41586-019-0969-x","article-title":"The single-cell transcriptional landscape of mammalian organogenesis","volume":"566","author":"Cao","year":"2019","journal-title":"Nature"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"979","DOI":"10.1038\/nmeth.4402","article-title":"Reversed graph embedding resolves complex single-cell trajectories","volume":"14","author":"Qiu","year":"2017","journal-title":"Nat. Methods"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1363","DOI":"10.1101\/gr.240663.118","article-title":"Benchmark and integration of resources for the estimation of human transcription factor activities","volume":"29","author":"Holland","year":"2019","journal-title":"Genome Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1016\/j.healun.2006.10.005","article-title":"Decorin-mediated transforming growth factor-beta inhibition ameliorates adverse cardiac remodeling","volume":"26","author":"Jahanyar","year":"2007","journal-title":"J. Heart Lung Transplant."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2708","DOI":"10.1161\/ATVBAHA.121.316615","article-title":"Pcpe2, a Novel Extracellular Matrix Protein, Regulates Adipocyte SR-BI-Mediated High-Density Lipoprotein Uptake","volume":"41","author":"Xu","year":"2021","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"2852","DOI":"10.1073\/pnas.1215779110","article-title":"Latent TGF-beta binding protein 4 promotes elastic fiber assembly by interacting with fibulin-5","volume":"110","author":"Noda","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Wan, J., Zhang, G., Li, X., Qiu, X., Ouyang, J., Dai, J., and Min, S. (2021). Matrix Metalloproteinase 3: A Promoting and Destabilizing Factor in the Pathogenesis of Disease and Cell Differentiation. Front. Physiol., 12.","DOI":"10.3389\/fphys.2021.663978"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"4581","DOI":"10.1074\/jbc.R100037200","article-title":"Hyaluronan and homeostasis: A balancing act","volume":"277","author":"Tammi","year":"2002","journal-title":"J. Biol. Chem."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Wight, T.N., Kang, I., Evanko, S.P., Harten, I.A., Chang, M.Y., Pearce, O.M.T., Allen, C.E., and Frevert, C.W. (2020). Versican-A Critical Extracellular Matrix Regulator of Immunity and Inflammation. Front. Immunol., 11.","DOI":"10.3389\/fimmu.2020.00512"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1161\/01.ATV.0000149141.81230.c6","article-title":"Vascular injury induces expression of periostin: Implications for vascular cell differentiation and migration","volume":"25","author":"Lindner","year":"2005","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"12260","DOI":"10.1038\/ncomms12260","article-title":"Genetic lineage tracing defines myofibroblast origin and function in the injured heart","volume":"7","author":"Kanisicak","year":"2016","journal-title":"Nat. Commun."},{"key":"ref_30","first-page":"321","article-title":"ATF3 and stress responses","volume":"7","author":"Hai","year":"1999","journal-title":"Gene Expr."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1016\/j.exphem.2019.03.003","article-title":"Transcriptional regulators CITED2 and PU.1 cooperate in maintaining hematopoietic stem cells","volume":"73","author":"Mattes","year":"2019","journal-title":"Exp. Hematol."},{"key":"ref_32","first-page":"269","article-title":"The structure and function of the urokinase receptor, a membrane protein governing plasminogen activation on the cell surface","volume":"376","author":"Behrendt","year":"1995","journal-title":"Biol. Chem."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Zhao, Y., Huang, Z., Gao, L., Ma, H., and Chang, R. (2024). Osteopontin\/SPP1: A potential mediator between immune cells and vascular calcification. Front. Immunol., 15.","DOI":"10.3389\/fimmu.2024.1395596"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"9135","DOI":"10.2147\/JIR.S478413","article-title":"Multi-Omics Exploration of the Role of PTGS2 as a Hub Gene in Ferroptosis Within the Artery of Takayasu Arteritis","volume":"17","author":"Gao","year":"2024","journal-title":"J. Inflamm. Res."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"178","DOI":"10.1016\/j.matbio.2012.01.006","article-title":"Thrombospondin1 in tissue repair and fibrosis: TGF-beta-dependent and independent mechanisms","volume":"31","author":"Sweetwyne","year":"2012","journal-title":"Matrix Biol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"2081","DOI":"10.1172\/JCI131335","article-title":"Transcription factor c-Maf is a checkpoint that programs macrophages in lung cancer","volume":"130","author":"Liu","year":"2020","journal-title":"J. Clin. Investig."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"E337","DOI":"10.1073\/pnas.1614926114","article-title":"GAS6 is a key homeostatic immunological regulator of host-commensal interactions in the oral mucosa","volume":"114","author":"Nassar","year":"2017","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1449","DOI":"10.2174\/1381612822666151210122954","article-title":"Coagulation Factor XIIIA (F13A1): Novel Perspectives in Treatment and Pharmacogenetics","volume":"22","author":"Gemmati","year":"2016","journal-title":"Curr. Pharm. Des."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"100124","DOI":"10.1016\/j.ocarto.2020.100124","article-title":"Recombinant human gelsolin promotes the migration of human articular cartilage chondrocytes by regulating gene expression in vitro","volume":"2","author":"Feldt","year":"2020","journal-title":"Osteoarthr. Cartil. Open"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"896","DOI":"10.1161\/CIRCRESAHA.108.172882","article-title":"Gelsolin regulates cardiac remodeling after myocardial infarction through DNase I-mediated apoptosis","volume":"104","author":"Li","year":"2009","journal-title":"Circ. Res."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"599","DOI":"10.1161\/01.CIR.0000023532.98469.48","article-title":"Macrophage depletion by clodronate-containing liposomes reduces neointimal formation after balloon injury in rats and rabbits","volume":"106","author":"Danenberg","year":"2002","journal-title":"Circulation"},{"key":"ref_42","first-page":"28","article-title":"Thrombospondin-1 regulation of latent TGF-beta activation: A therapeutic target for fibrotic disease","volume":"68\u201369","author":"Suto","year":"2018","journal-title":"Matrix Biol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"19684","DOI":"10.1038\/srep19684","article-title":"Secreted Thrombospondin-1 Regulates Macrophage Interleukin-1beta Production and Activation through CD47","volume":"6","author":"Stein","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Uhlig, M., Billig, S., Wienhold, J., and Schumacher, D. (2025). Pro-Fibrotic Macrophage Subtypes: SPP1+ Macrophages as a Key Player and Therapeutic Target in Cardiac Fibrosis?. Cells, 14.","DOI":"10.3390\/cells14050345"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1016\/j.kint.2015.12.021","article-title":"Angiopoietin-like protein 2 increases renal fibrosis by accelerating transforming growth factor-\u03b2 signaling in chronic kidney disease","volume":"89","author":"Morinaga","year":"2016","journal-title":"Kidney Int."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"eadn6068","DOI":"10.1126\/sciadv.adn6068","article-title":"Renal Angptl4 is a key fibrogenic molecule in progressive diabetic kidney disease","volume":"10","author":"Srivastava","year":"2024","journal-title":"Sci. Adv."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"113692","DOI":"10.1016\/j.isci.2025.113692","article-title":"Angiopoietin-like protein 7: A narrative review and its potential roles in post-myocardial infarction fibrosis","volume":"28","author":"Chen","year":"2025","journal-title":"iScience"}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/14\/24\/1998\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,18]],"date-time":"2025-12-18T05:18:59Z","timestamp":1766035139000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/14\/24\/1998"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,12,16]]},"references-count":47,"journal-issue":{"issue":"24","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["cells14241998"],"URL":"https:\/\/doi.org\/10.3390\/cells14241998","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,12,16]]}}}