{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T08:27:13Z","timestamp":1791620833844,"version":"4.3.4"},"reference-count":59,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,4,7]],"date-time":"2026-04-07T00:00:00Z","timestamp":1775520000000},"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. Cardiovasc. Med."],"abstract":"\n Introduction<\/jats:title>\n Aortic valve disease (AVD) is a cardiovascular disorder highly prevalent in the elderly population. Aortic valve leaflets suffer hardening due to extracellular matrix (ECM) remodeling and subsequent calcification, leading to impaired blood flow and aortic valve stenosis. Valve interstitial cells (VICs) are fibroblast-like cells that can undergo myofibroblast activation and osteogenic transformation, contributing to disease progression.<\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n We performed a bioinformatic re-analysis of a publicly available scRNA-seq dataset to identify pathogenic VIC subpopulations and characterize cell-cell communication networks relevant to early AVD.<\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n Re-analysis of scRNA-seq data from aortic valves of\n Apoe<\/jats:italic>\n \u2212\/\u2212<\/jats:sup>\n and\n Ldlr<\/jats:italic>\n \u2212\/\u2212<\/jats:sup>\n mice revealed a distinct VIC subpopulation enriched in osteopontin (\n Spp1<\/jats:italic>\n ), fibromodulin (\n Fmod<\/jats:italic>\n ), and chondrocyte-specific genes, including\n Chad<\/jats:italic>\n ,\n Comp<\/jats:italic>\n , and\n Cilp2<\/jats:italic>\n . Differential expression and gene ontology enrichment analyses indicated a strong signature of ECM organization and remodeling in this cluster under atherosclerotic conditions. Cell-cell communication analysis using CellChat showed enhanced intercellular signaling involving the VIC Spp1\n +<\/jats:sup>\n cluster. Moreover, incoming interaction strength was increased through collagen, fibronectin, Spp1, and cyclophilin A (CypA) signaling pathways, while the thrombospondin pathway was decreased. NicheNet analysis suggested a crosstalk between VICs Spp1\n +<\/jats:sup>\n with immune and valvular cells via receptors such as\n Icam1<\/jats:italic>\n ,\n Itgav<\/jats:italic>\n ,\n osteoprotegerin<\/jats:italic>\n ,\n Sdc4<\/jats:italic>\n , and\n Itga10<\/jats:italic>\n . Moreover, gene regulatory network reconstruction using pySCENIC identified NFE2L1 as a shared transcriptional regulator in both hyperlipidemic conditions, potentially driving the fibrotic program in VIC Spp1\n +<\/jats:sup>\n across both models.\n <\/jats:p>\n <\/jats:sec>\n \n Discussion<\/jats:title>\n \n These findings suggests the presence of a disease-associated VIC Spp1\n +<\/jats:sup>\n subpopulation, that may contribute to valve sclerosis through ECM remodeling and deposition, providing mechanistic insights into early valve sclerosis.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.3389\/fcvm.2026.1755830","type":"journal-article","created":{"date-parts":[[2026,4,7]],"date-time":"2026-04-07T04:15:19Z","timestamp":1775535319000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Osteopontin-expressing valvular interstitial cell subpopulation as a driver of extracellular matrix remodeling in aortic valve disease"],"prefix":"10.3389","volume":"13","author":[{"given":"R\u0103zvan D.","family":"Macarie","sequence":"first","affiliation":[{"name":"Inflammation Department, Institute of Cellular Biology and Pathology \u201cNicolae Simionescu\u201d","place":["Bucharest, Romania"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monica M.","family":"\u021aucureanu","sequence":"additional","affiliation":[{"name":"Inflammation Department, Institute of Cellular Biology and Pathology \u201cNicolae Simionescu\u201d","place":["Bucharest, Romania"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leti\u021bia","family":"Ciortan","sequence":"additional","affiliation":[{"name":"Inflammation Department, Institute of Cellular Biology and Pathology \u201cNicolae Simionescu\u201d","place":["Bucharest, Romania"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mihai Bogdan","family":"Preda","sequence":"additional","affiliation":[{"name":"Stem Cell Biology Department, Institute of Cellular Biology and Pathology \u201cNicolae Simionescu\u201d","place":["Bucharest, Romania"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ileana","family":"M\u00e2ndu\u021beanu","sequence":"additional","affiliation":[{"name":"Inflammation Department, Institute of Cellular Biology and Pathology \u201cNicolae Simionescu\u201d","place":["Bucharest, Romania"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena","family":"Butoi","sequence":"additional","affiliation":[{"name":"Inflammation Department, Institute of Cellular Biology and Pathology \u201cNicolae Simionescu\u201d","place":["Bucharest, Romania"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,4,7]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"683","DOI":"10.1093\/eurheartj\/ehab757","article-title":"Calcific aortic valve disease: from molecular and cellular mechanisms to medical therapy","volume":"43","author":"Kraler","year":"2022","journal-title":"Eur Heart J"},{"key":"B2","doi-asserted-by":"publisher","first-page":"1116","DOI":"10.1093\/eurheartj\/ehae043","article-title":"Transcatheter or surgical aortic valve implantation: 10-year outcomes of the NOTION trial","volume":"45","author":"Thyregod","year":"2024","journal-title":"Eur Heart J"},{"key":"B3","doi-asserted-by":"publisher","first-page":"1344","DOI":"10.1161\/CIRCRESAHA.121.318011","article-title":"Inflammatory and biomechanical drivers of endothelial-interstitial interactions in calcific aortic valve disease","volume":"128","author":"Driscoll","year":"2021","journal-title":"Circ Res"},{"key":"B4","doi-asserted-by":"publisher","first-page":"e006339","DOI":"10.1161\/JAHA.117.006339","article-title":"Valve interstitial cells: the key to understanding the pathophysiology of heart valve calcification","volume":"6","author":"Rutkovskiy","year":"2017","journal-title":"J Am Heart Assoc"},{"key":"B5","doi-asserted-by":"publisher","first-page":"16006","DOI":"10.1038\/nrdp.2016.6","article-title":"Calcific aortic stenosis","volume":"2","author":"Lindman","year":"2016","journal-title":"Nat Rev Dis Primers"},{"key":"B6","doi-asserted-by":"publisher","first-page":"844","DOI":"10.1161\/01.CIR.90.2.844","article-title":"Characterization of the early lesion of \u2018degenerative\u2019 valvular aortic stenosis. Histological and immunohistochemical studies","volume":"90","author":"Otto","year":"1994","journal-title":"Circulation"},{"key":"B7","doi-asserted-by":"publisher","first-page":"3316","DOI":"10.1161\/CIRCULATIONAHA.104.486738","article-title":"Spectrum of calcific aortic valve disease: pathogenesis, disease progression, and treatment strategies","volume":"111","author":"Freeman","year":"2005","journal-title":"Circulation"},{"key":"B8","doi-asserted-by":"publisher","first-page":"6","DOI":"10.1186\/s13619-024-00189-8","article-title":"Models for calcific aortic valve disease in vivo and in vitro","volume":"13","author":"Zhu","year":"2024","journal-title":"Cell Regen"},{"key":"B9","doi-asserted-by":"publisher","first-page":"183","DOI":"10.6515\/ACS.202005_36(3).20200213A","article-title":"Endothelial-to-Mesenchymal transition in calcific aortic valve disease","volume":"36","author":"Ma","year":"2020","journal-title":"Acta Cardiol Sin"},{"key":"B10","doi-asserted-by":"publisher","first-page":"183","DOI":"10.1016\/j.carpath.2010.09.008","article-title":"The response to valve injury. A paradigm to understand the pathogenesis of heart valve disease","volume":"20","author":"Li","year":"2011","journal-title":"Cardiovasc Pathol"},{"key":"B11","doi-asserted-by":"publisher","first-page":"377","DOI":"10.1161\/CIRCULATIONAHA.117.032291","article-title":"Spatiotemporal multi-omics mapping generates a molecular atlas of the aortic valve and reveals networks driving disease","volume":"138","author":"Schlotter","year":"2018","journal-title":"Circulation"},{"key":"B12","doi-asserted-by":"publisher","first-page":"5461","DOI":"10.1038\/s41467-022-33202-2","article-title":"Single-cell transcriptomics reveal cellular diversity of aortic valve and the immunomodulation by PPARgamma during hyperlipidemia","volume":"13","author":"Lee","year":"2022","journal-title":"Nat Commun"},{"key":"B13","doi-asserted-by":"publisher","first-page":"293","DOI":"10.1038\/s41587-023-01767-y","article-title":"Dictionary learning for integrative, multimodal and scalable single-cell analysis","volume":"42","author":"Hao","year":"2024","journal-title":"Nat Biotechnol"},{"key":"B14","article-title":"EnhancedVolcano: Publication-ready volcano plots with enhanced colouring and labeling","author":"Blighe","year":"2023"},{"key":"B15","doi-asserted-by":"publisher","first-page":"100141","DOI":"10.1016\/j.xinn.2021.100141","article-title":"Clusterprofiler 4.0: a universal enrichment tool for interpreting omics data","volume":"2","author":"Wu","year":"2021","journal-title":"The Innovation"},{"key":"B16","doi-asserted-by":"publisher","first-page":"159","DOI":"10.1038\/s41592-019-0667-5","article-title":"Nichenet: modeling intercellular communication by linking ligands to target genes","volume":"17","author":"Browaeys","year":"2020","journal-title":"Nat Methods"},{"key":"B17","doi-asserted-by":"publisher","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":"B18","doi-asserted-by":"publisher","first-page":"1355","DOI":"10.1038\/s41592-023-01938-4","article-title":"SCENIC+: single-cell multiomic inference of enhancers and gene regulatory networks","volume":"20","author":"Bravo Gonzalez-Blas","year":"2023","journal-title":"Nat Methods"},{"key":"B19","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1186\/s13059-017-1382-0","article-title":"SCANPY: large-scale single-cell gene expression data analysis","volume":"19","author":"Wolf","year":"2018","journal-title":"Genome Biol"},{"key":"B20","article-title":"cisTarget databases [Internet]","year":"2023"},{"key":"B21","doi-asserted-by":"crossref","DOI":"10.32614\/CRAN.package.pheatmap","article-title":"pheatmap: Pretty Heatmaps","author":"Kolde","year":""},{"key":"B22","doi-asserted-by":"publisher","first-page":"562","DOI":"10.1177\/1479164119874469","article-title":"Diabetes-induced early molecular and functional changes in aortic heart valves in a murine model of atherosclerosis","volume":"16","author":"Tucureanu","year":"2019","journal-title":"Diab Vasc Dis Res"},{"key":"B23","doi-asserted-by":"publisher","first-page":"2139","DOI":"10.1002\/jcp.22549","article-title":"Osteopontin controls endothelial cell migration in vitro and in excised human valvular tissue from patients with calcific aortic stenosis and controls","volume":"226","author":"Poggio","year":"2011","journal-title":"J Cell Physiol"},{"key":"B24","doi-asserted-by":"publisher","first-page":"125","DOI":"10.1177\/00220345221138525","article-title":"Fibromodulin, a multifunctional matricellular modulator","volume":"102","author":"Zheng","year":"2023","journal-title":"J Dent Res"},{"key":"B25","doi-asserted-by":"publisher","first-page":"1029","DOI":"10.1002\/dvdy.24435","article-title":"Development of myotendinous-like junctions that anchor cardiac valves requires fibromodulin and lumican","volume":"245","author":"Dupuis","year":"2016","journal-title":"Dev Dyn"},{"key":"B26","doi-asserted-by":"publisher","first-page":"e82243","DOI":"10.1371\/journal.pone.0082243","article-title":"Localization of microfibrillar-associated protein 4 (MFAP4) in human tissues: clinical evaluation of serum MFAP4 and its association with various cardiovascular conditions","volume":"8","author":"Wulf-Johansson","year":"2013","journal-title":"PLoS One"},{"key":"B27","doi-asserted-by":"publisher","first-page":"e350","DOI":"10.1161\/ATVBAHA.120.314913","article-title":"Myeloid-Derived TSP1 (thrombospondin-1) contributes to abdominal aortic aneurysm through suppressing tissue inhibitor of metalloproteinases-1","volume":"40","author":"Yang","year":"2020","journal-title":"Arterioscler Thromb Vasc Biol"},{"key":"B28","doi-asserted-by":"publisher","first-page":"28","DOI":"10.1016\/j.matbio.2017.12.009","article-title":"Thrombospondin-1 regulation of latent TGF-beta activation: a therapeutic target for fibrotic disease","author":"Murphy-Ullrich","year":"2018","journal-title":"Matrix Biol"},{"key":"B29","doi-asserted-by":"publisher","first-page":"2086","DOI":"10.1161\/ATVBAHA.113.303017","article-title":"Osteopontin-CD44v6 interaction mediates calcium deposition via phospho-akt in valve interstitial cells from patients with noncalcified aortic valve sclerosis","volume":"34","author":"Poggio","year":"2014","journal-title":"Arterioscler Thromb Vasc Biol"},{"key":"B30","doi-asserted-by":"publisher","first-page":"1395596","DOI":"10.3389\/fimmu.2024.1395596","article-title":"Osteopontin\/SPP1: a potential mediator between immune cells and vascular calcification","volume":"15","author":"Zhao","year":"2024","journal-title":"Front Immunol"},{"key":"B31","doi-asserted-by":"publisher","first-page":"102819","DOI":"10.1016\/j.redox.2023.102819","article-title":"Unravelling the role of NFE2L1 in stress responses and related diseases","volume":"65","author":"Liu","year":"2023","journal-title":"Redox Biol"},{"key":"B32","doi-asserted-by":"publisher","first-page":"1094","DOI":"10.1016\/j.cell.2017.10.003","article-title":"NRF1 Is an ER membrane sensor that is central to cholesterol homeostasis","volume":"171","author":"Widenmaier","year":"2017","journal-title":"Cell"},{"key":"B33","doi-asserted-by":"publisher","first-page":"7235","DOI":"10.1073\/pnas.0802301105","article-title":"Alternative translation of osteopontin generates intracellular and secreted isoforms that mediate distinct biological activities in dendritic cells","volume":"105","author":"Shinohara","year":"2008","journal-title":"Proc Natl Acad Sci U S A"},{"key":"B34","doi-asserted-by":"publisher","first-page":"2163","DOI":"10.1161\/01.CIR.92.8.2163","article-title":"Osteopontin is expressed in human aortic valvular lesions","volume":"92","author":"O'Brien","year":"1995","journal-title":"Circulation"},{"key":"B35","doi-asserted-by":"publisher","first-page":"e26769","DOI":"10.1371\/journal.pone.0026769","article-title":"Sox9 transcriptionally represses Spp1 to prevent matrix mineralization in maturing heart valves and chondrocytes","volume":"6","author":"Peacock","year":"2011","journal-title":"PLoS One"},{"key":"B36","doi-asserted-by":"publisher","first-page":"3573","DOI":"10.3390\/cimb44080245","article-title":"Clinical and molecular implications of osteopontin in heart failure","volume":"44","author":"Mamazhakypov","year":"2022","journal-title":"Curr Issues Mol Biol"},{"key":"B37","doi-asserted-by":"publisher","first-page":"196","DOI":"10.1016\/j.jtcvs.2008.10.045","article-title":"Correlation between plasma osteopontin levels and aortic valve calcification: potential insights into the pathogenesis of aortic valve calcification and stenosis","volume":"138","author":"Yu","year":"2009","journal-title":"J Thorac Cardiovasc Surg"},{"key":"B38","doi-asserted-by":"publisher","first-page":"292","DOI":"10.1016\/j.ydbio.2006.03.027","article-title":"Hearts and bones: shared regulatory mechanisms in heart valve, cartilage, tendon, and bone development","volume":"294","author":"Lincoln","year":"2006","journal-title":"Dev Biol"},{"key":"B39","doi-asserted-by":"publisher","first-page":"22549","DOI":"10.1074\/jbc.M111.335935","article-title":"Collagen XII and XIV, new partners of cartilage oligomeric matrix protein in the skin extracellular matrix suprastructure","volume":"287","author":"Agarwal","year":"2012","journal-title":"J Biol Chem"},{"key":"B40","doi-asserted-by":"publisher","first-page":"325","DOI":"10.1016\/j.matbio.2013.02.010","article-title":"Enhanced deposition of cartilage oligomeric matrix protein is a common feature in fibrotic skin pathologies","volume":"32","author":"Agarwal","year":"2013","journal-title":"Matrix Biol"},{"key":"B41","doi-asserted-by":"publisher","first-page":"dev173047","DOI":"10.1242\/dev.173047","article-title":"Maturation of heart valve cell populations during postnatal remodeling","volume":"146","author":"Hulin","year":"2019","journal-title":"Development"},{"key":"B42","doi-asserted-by":"publisher","first-page":"25","DOI":"10.1016\/j.jacbts.2020.11.008","article-title":"Proteomic architecture of valvular extracellular matrix: fNDC1 and MXRA5 are new biomarkers of aortic stenosis","volume":"6","author":"Bouchareb","year":"2021","journal-title":"JACC Basic Transl Sci"},{"key":"B43","doi-asserted-by":"publisher","first-page":"61","DOI":"10.1007\/978-94-017-9153-3_4","article-title":"Integrin alpha10beta1: a collagen receptor critical in skeletal development","volume":"819","author":"Lundgren-Akerlund","year":"2014","journal-title":"Adv Exp Med Biol"},{"key":"B44","doi-asserted-by":"publisher","first-page":"217","DOI":"10.1093\/cvr\/cvv002","article-title":"Syndecan-4 is a key determinant of collagen cross-linking and passive myocardial stiffness in the pressure-overloaded heart","volume":"106","author":"Herum","year":"2015","journal-title":"Cardiovasc Res"},{"key":"B45","doi-asserted-by":"publisher","first-page":"e013518","DOI":"10.1161\/JAHA.119.013518","article-title":"Syndecan-4 protects the heart from the profibrotic effects of thrombin-cleaved osteopontin","volume":"9","author":"Herum","year":"2020","journal-title":"J Am Heart Assoc"},{"key":"B46","doi-asserted-by":"publisher","first-page":"e65201","DOI":"10.1371\/journal.pone.0065201","article-title":"Osteoprotegerin inhibits aortic valve calcification and preserves valve function in hypercholesterolemic mice","volume":"8","author":"Weiss","year":"2013","journal-title":"PLoS One"},{"key":"B47","doi-asserted-by":"publisher","first-page":"39","DOI":"10.1002\/reg2.77","article-title":"Macrophages and fibroblasts during inflammation and tissue repair in models of organ regeneration","volume":"4","author":"Mescher","year":"2017","journal-title":"Regeneration"},{"key":"B48","doi-asserted-by":"publisher","first-page":"2744","DOI":"10.1016\/j.bbamcr.2014.07.017","article-title":"Ligation of ICAM-1 on human aortic valve interstitial cells induces the osteogenic response: a critical role of the Notch1-NF-kappaB pathway in BMP-2 expression","volume":"1843","author":"Wang","year":"2014","journal-title":"Biochim Biophys Acta"},{"key":"B49","doi-asserted-by":"publisher","first-page":"91","DOI":"10.1016\/j.atherosclerosis.2005.11.034","article-title":"Type I and type III collagen synthesis and composition in the valve matrix in aortic valve stenosis","volume":"189","author":"Eriksen","year":"2006","journal-title":"Atherosclerosis"},{"key":"B50","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1186\/1471-2261-14-29","article-title":"Manipulation of valve composition to elucidate the role of collagen in aortic valve calcification","volume":"14","author":"Rodriguez","year":"2014","journal-title":"BMC Cardiovasc Disord"},{"key":"B51","doi-asserted-by":"publisher","first-page":"1028","DOI":"10.1016\/j.jacbts.2023.01.009","article-title":"Focusing on the native matrix proteins in calcific aortic valve stenosis","volume":"8","author":"Anousakis-Vlachochristou","year":"2023","journal-title":"JACC Basic Transl Sci"},{"key":"B52","doi-asserted-by":"publisher","first-page":"203","DOI":"10.1016\/j.carpath.2007.02.008","article-title":"Cardiac valve interstitial cells secrete fibronectin and form fibrillar adhesions in response to injury","volume":"16","author":"Fayet","year":"2007","journal-title":"Cardiovasc Pathol"},{"key":"B53","doi-asserted-by":"publisher","first-page":"3799","DOI":"10.1242\/jcs.124636","article-title":"Syndecan-4 signaling at a glance","volume":"126","author":"Elfenbein","year":"2013","journal-title":"J Cell Sci"},{"key":"B54","doi-asserted-by":"publisher","first-page":"66","DOI":"10.1006\/abbi.1999.1607","article-title":"Syndecan-4 binding to the high affinity heparin-binding domain of fibronectin drives focal adhesion formation in fibroblasts","volume":"374","author":"Woods","year":"2000","journal-title":"Arch Biochem Biophys"},{"key":"B55","doi-asserted-by":"publisher","first-page":"5670","DOI":"10.1091\/mbc.e04-08-0759","article-title":"Coregulation of fibronectin signaling and matrix contraction by tenascin-C and syndecan-4","volume":"15","author":"Midwood","year":"2004","journal-title":"Mol Biol Cell"},{"key":"B56","doi-asserted-by":"publisher","first-page":"2345","DOI":"10.1161\/ATVBAHA.112.300226","article-title":"Endoplasmic reticulum stress participates in aortic valve calcification in hypercholesterolemic animals","volume":"33","author":"Cai","year":"2013","journal-title":"Arterioscler Thromb Vasc Biol"},{"key":"B57","doi-asserted-by":"publisher","first-page":"5189","DOI":"10.7150\/thno.71813","article-title":"The mechanistic pathways of oxidative stress in aortic stenosis and clinical implications","volume":"12","author":"Phua","year":"2022","journal-title":"Theranostics"},{"key":"B58","doi-asserted-by":"publisher","first-page":"113889","DOI":"10.1016\/j.yexcr.2023.113889","article-title":"BFGF Attenuates aortic valvular interstitial cell calcification by inhibiting endoplasmic reticulum stress-mediated apoptosis","volume":"434","author":"Yuan","year":"2024","journal-title":"Exp Cell Res"},{"key":"B59","doi-asserted-by":"publisher","first-page":"110685","DOI":"10.1016\/j.celrep.2022.110685","article-title":"A disease-driver population within interstitial cells of human calcific aortic valves identified via single-cell and proteomic profiling","volume":"39","author":"Decano","year":"2022","journal-title":"Cell Rep"}],"container-title":["Frontiers in Cardiovascular Medicine"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcvm.2026.1755830\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,7]],"date-time":"2026-04-07T04:15:23Z","timestamp":1775535323000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcvm.2026.1755830\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4,7]]},"references-count":59,"alternative-id":["10.3389\/fcvm.2026.1755830"],"URL":"https:\/\/doi.org\/10.3389\/fcvm.2026.1755830","relation":{},"ISSN":["2297-055X"],"issn-type":[{"value":"2297-055X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,4,7]]},"article-number":"1755830"}}