{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T11:08:55Z","timestamp":1785150535510,"version":"3.55.0"},"reference-count":60,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"5","license":[{"start":{"date-parts":[[2025,5,1]],"date-time":"2025-05-01T00:00:00Z","timestamp":1746057600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["ATVB"],"published-print":{"date-parts":[[2025,5]]},"abstract":"<jats:sec>\n                    <jats:title>BACKGROUND:<\/jats:title>\n                    <jats:p>Genome-wide association studies have identified common genetic variants at \u2248300 human genomic loci linked to coronary artery disease susceptibility. Among these genomic regions, the most impactful is the 9p21.3 coronary artery disease risk locus, which spans a 60-kb gene desert and encompasses \u224880 SNPs (single nucleotide polymorphism) in high linkage disequilibrium. Despite \u22482 decades since its discovery, the role of the 9p21.3 locus in cells of the vasculature remains incompletely resolved.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS:<\/jats:title>\n                    <jats:p>\n                      We differentiated induced pluripotent stem cells (iPSCs) from risk, nonrisk donors at 9p21.3, and isogenic knockouts into vascular smooth muscle cells (VSMCs). We performed single-cell transcriptomic profiling, including coembedding and comparison with publicly available human arterial data sets. We conducted functional characterization using migration and calcification assays and confirmed our findings on iPSC\u2013VSMCs derived from additional donors. Finally, we used overexpression of\n                      <jats:italic>ANRIL<\/jats:italic>\n                      followed by gene expression analysis.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS:<\/jats:title>\n                    <jats:p>\n                      We demonstrated that iPSC\u2013VSMCs harboring the 9p21.3 risk haplotype preferentially adopt an osteochondrogenic state and show remarkable similarity to fibrochondrocytes from human artery tissue. The transcriptional profile and functional assessment of migration and calcification capacity across iPSC\u2013VSMC lines from multiple donors concordantly resemble an osteochondrogenic state. Importantly, we identified numerous transcription factors driving different VSMC state trajectories. Additionally, we prioritized\n                      <jats:italic>LIMCH1<\/jats:italic>\n                      and\n                      <jats:italic>CRABP1<\/jats:italic>\n                      as signature genes critical for defining the risk transcriptional program. Finally, overexpression of a short isoform of\n                      <jats:italic>ANRIL<\/jats:italic>\n                      in 9p21.3 knockout cells was sufficient to induce the osteochondrogenic transcriptional signature.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSIONS:<\/jats:title>\n                    <jats:p>\n                      Our study provides new insights into the mechanism of the 9p21.3 risk locus and defines its previously undescribed role in driving a disease-prone transcriptional and functional state in VSMCs concordant with an osteochondrogenic-like state. Our data suggest that the 9p21.3 risk haplotype likely promotes arterial calcification, through altered expression of\n                      <jats:italic>ANRIL<\/jats:italic>\n                      , in a cell type\u2013specific and cell-autonomous manner, providing insight into potential risk assessment and treatment for carriers.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/atvbaha.124.322045","type":"journal-article","created":{"date-parts":[[2025,3,27]],"date-time":"2025-03-27T05:03:36Z","timestamp":1743051816000},"page":"702-721","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":11,"title":["The 9p21.3 Coronary Artery Disease Risk Locus Drives Vascular Smooth Muscle Cells to an Osteochondrogenic State"],"prefix":"10.1161","volume":"45","author":[{"given":"Elsa","family":"Salido","sequence":"first","affiliation":[{"name":"Department of Cell and Regenerative Biology, University of Wisconsin-Madison, Madison (E.S., C.d.M.V., R.Z., P.P., S.S., V.L.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carolina","family":"de Medeiros Vieira","sequence":"additional","affiliation":[{"name":"Department of Cell and Regenerative Biology, University of Wisconsin-Madison, Madison (E.S., C.d.M.V., R.Z., P.P., S.S., V.L.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2816-2250","authenticated-orcid":true,"given":"Jose Verdezoto","family":"Mosquera","sequence":"additional","affiliation":[{"name":"Department of Genome Sciences, and Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville (J.V.M., C.L.M.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rohan","family":"Zade","sequence":"additional","affiliation":[{"name":"Department of Cell and Regenerative Biology, University of Wisconsin-Madison, Madison (E.S., C.d.M.V., R.Z., P.P., S.S., V.L.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-6696-934X","authenticated-orcid":true,"given":"Parth","family":"Parikh","sequence":"additional","affiliation":[{"name":"Department of Cell and Regenerative Biology, University of Wisconsin-Madison, Madison (E.S., C.d.M.V., R.Z., P.P., S.S., V.L.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4185-1859","authenticated-orcid":true,"given":"Shraddha","family":"Suryavanshi","sequence":"additional","affiliation":[{"name":"Department of Cell and Regenerative Biology, University of Wisconsin-Madison, Madison (E.S., C.d.M.V., R.Z., P.P., S.S., V.L.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4276-3607","authenticated-orcid":true,"given":"Clint L.","family":"Miller","sequence":"additional","affiliation":[{"name":"Department of Genome Sciences, and Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville (J.V.M., C.L.M.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0573-9878","authenticated-orcid":true,"given":"Valentina","family":"Lo Sardo","sequence":"additional","affiliation":[{"name":"Department of Cell and Regenerative Biology, University of Wisconsin-Madison, Madison (E.S., C.d.M.V., R.Z., P.P., S.S., V.L.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-022-01070-7"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1038\/s44161-023-00375-y"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-020-0705-3"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3396"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gky1120"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tig.2021.06.007"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1142842"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1142447"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1056\/nejmoa072366"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2018.01262"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2148-13-247"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature08801"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00041.2003"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-physiol-012110-142315"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41569-019-0227-9"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.120.048378"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1161\/atvbaha.120.315373"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-022-01142-8"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-019-0512-5"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2023.113380"},{"key":"e_1_3_3_22_2","doi-asserted-by":"publisher","DOI":"10.1038\/s44161-022-00042-8"},{"key":"e_1_3_3_23_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.115.304634"},{"key":"e_1_3_3_24_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.108.183053"},{"key":"e_1_3_3_25_2","doi-asserted-by":"publisher","DOI":"10.1002\/path.1743"},{"key":"e_1_3_3_26_2","doi-asserted-by":"publisher","DOI":"10.1038\/nbt.3749"},{"key":"e_1_3_3_27_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2018.11.014"},{"key":"e_1_3_3_28_2","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2014.059"},{"key":"e_1_3_3_29_2","doi-asserted-by":"publisher","DOI":"10.1161\/circresaha.120.317415"},{"key":"e_1_3_3_30_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.aaz1776"},{"key":"e_1_3_3_31_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2217122120"},{"key":"e_1_3_3_32_2","doi-asserted-by":"publisher","DOI":"10.1161\/jaha.123.031121"},{"key":"e_1_3_3_33_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.120.049922"},{"key":"e_1_3_3_34_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1232341100"},{"key":"e_1_3_3_35_2","doi-asserted-by":"publisher","DOI":"10.7555\/JBR.29.20140151"},{"key":"e_1_3_3_36_2","doi-asserted-by":"publisher","DOI":"10.1038\/nm.3866"},{"key":"e_1_3_3_37_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.120.046672"},{"key":"e_1_3_3_38_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.115.306361"},{"key":"e_1_3_3_39_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1735526100"},{"key":"e_1_3_3_40_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.123.323365"},{"key":"e_1_3_3_41_2","first-page":"e75","article-title":"Vascular smooth muscle cell motility: from migration to invasion.","volume":"15","author":"Louis SF","year":"2010","unstructured":"Louis SF, Zahradka P. Vascular smooth muscle cell motility: from migration to invasion. Exp Clin Cardiol. 2010;15:e75\u2013e85.","journal-title":"Exp Clin Cardiol"},{"key":"e_1_3_3_42_2","doi-asserted-by":"publisher","DOI":"10.1161\/atvbaha.115.305044"},{"key":"e_1_3_3_43_2","doi-asserted-by":"publisher","DOI":"10.1093\/cvr\/cvs115"},{"key":"e_1_3_3_44_2","doi-asserted-by":"publisher","DOI":"10.1161\/circresaha.117.312086"},{"key":"e_1_3_3_45_2","doi-asserted-by":"publisher","DOI":"10.1093\/cvr\/cvy084"},{"key":"e_1_3_3_46_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCGENETICS.108.832527"},{"key":"e_1_3_3_47_2","doi-asserted-by":"publisher","DOI":"10.1111\/joim.12063"},{"key":"e_1_3_3_48_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.114.015023"},{"key":"e_1_3_3_49_2","doi-asserted-by":"publisher","DOI":"10.1161\/ATVBAHA.109.189522"},{"key":"e_1_3_3_50_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0005027"},{"key":"e_1_3_3_51_2","doi-asserted-by":"publisher","DOI":"10.1161\/ATVBAHA.109.196832"},{"key":"e_1_3_3_52_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1003588"},{"key":"e_1_3_3_53_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0007677"},{"key":"e_1_3_3_54_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.atherosclerosis.2010.06.029"},{"key":"e_1_3_3_55_2","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/dds224"},{"key":"e_1_3_3_56_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrg.2016.160"},{"key":"e_1_3_3_57_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.115.306566"},{"key":"e_1_3_3_58_2","doi-asserted-by":"publisher","DOI":"10.1002\/ana.21590"},{"key":"e_1_3_3_59_2","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.70246"},{"key":"e_1_3_3_60_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-019-1414-x"},{"key":"e_1_3_3_61_2","doi-asserted-by":"publisher","DOI":"10.1091\/mbc.E15-04-0218"}],"container-title":["Arteriosclerosis, Thrombosis, and Vascular Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.ahajournals.org\/doi\/full\/10.1161\/ATVBAHA.124.322045","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,4,23]],"date-time":"2025-04-23T14:01:12Z","timestamp":1745416872000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.ahajournals.org\/doi\/10.1161\/ATVBAHA.124.322045"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,5]]},"references-count":60,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2025,5]]}},"alternative-id":["10.1161\/ATVBAHA.124.322045"],"URL":"https:\/\/doi.org\/10.1161\/atvbaha.124.322045","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2024.05.25.595888","asserted-by":"object"}]},"ISSN":["1079-5642","1524-4636"],"issn-type":[{"value":"1079-5642","type":"print"},{"value":"1524-4636","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,5]]},"assertion":[{"value":"2024-10-22","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-03-12","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-03-27","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}