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The plaque-stabilizing fibrous cap is rich in VSMC-derived cells, yet the cellular transitions and regulatory mechanisms governing fibrous cap formation remain unclear. Here, we aimed to identify the VSMC phenotypic transitions associated with this critical process.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods and results<\/jats:title>\n                    <jats:p>Mapping of lineage-traced VSMCs during plaque development revealed investment of VSMCs prior to fibrous cap formation. Using single-cell RNA-sequencing (scRNA-seq) profiles of lineage-traced VSMCs from atherosclerotic and acutely injured mouse arteries, we identified a disease-specific VSMC state co-expressing contractile genes with extracellular matrix (ECM) components (including fibrillar collagens and elastin) and NOTCH3, which are associated with fibrous cap formation. Computational trajectory analysis predicted that this proposed fibrous cap-related VSMC (fcVSMC) state arises from a previously described plastic, intermediate VSMC population expressing SCA1 and VCAM1. Clonal analysis further showed that NOTCH3+ fcVSMCs derive from intermediate VSMCs in both atherosclerosis and an acute vascular injury model, suggesting a conserved disease-relevant mechanism. The fcVSMCs were enriched in plaque fibrous caps compared to lesion cores, consistent with a role in fibrous cap formation. By combining scRNA-seq trajectory analysis and spatial transcriptomics of human atherosclerotic plaques, we identified protease-activated receptor-1 (PAR1) as a candidate regulator of fcVSMC generation. PAR1 was expressed by VSMCs in human plaque fibrous caps and PAR1 activation by thrombin induced expression of contractile genes and ECM components associated with the fcVSMC state in human VSMCs.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Our findings identify a VSMC transition linked to fibrous cap formation in atherosclerosis and show this is modelled by vascular injury. We identify VSMC-expressed PAR1 as a potential therapeutic target for promoting plaque stability by driving the transition to the matrix-producing, fibrous cap-associated VSMC state.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/cvr\/cvaf112","type":"journal-article","created":{"date-parts":[[2025,6,26]],"date-time":"2025-06-26T07:54:11Z","timestamp":1750924451000},"page":"1359-1372","source":"Crossref","is-referenced-by-count":13,"title":["Delineation of a thrombin receptor-stimulated vascular smooth muscle cell transition generating cells in the plaque-stabilizing fibrous cap"],"prefix":"10.1093","volume":"121","author":[{"given":"James C K","family":"Taylor","sequence":"first","affiliation":[{"name":"Section of Cardiorespiratory Medicine, Department of Medicine, University of Cambridge, Victor Phillip Dahdaleh Heart and Lung Research Institute , Papworth Road, Cambridge CB2 0BB ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew 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,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4724-5200","authenticated-orcid":false,"given":"Jordi","family":"Lambert","sequence":"additional","affiliation":[{"name":"Section of Cardiorespiratory Medicine, Department of Medicine, University of Cambridge, Victor Phillip Dahdaleh Heart and Lung Research Institute , Papworth Road, Cambridge CB2 0BB ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Krishnaa T","family":"Mahbubani","sequence":"additional","affiliation":[{"name":"Collaborative Biorepository for Translational Medicine, Department of Surgery, University of Cambridge and NIHR Cambridge Biomedical Research Centre , Cambridge CB2 0QQ ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kirsty","family":"Foote","sequence":"additional","affiliation":[{"name":"Section of Cardiorespiratory Medicine, Department of Medicine, University of Cambridge, Victor Phillip Dahdaleh Heart and Lung Research Institute , Papworth Road, Cambridge CB2 0BB ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Allie","family":"Finigan","sequence":"additional","affiliation":[{"name":"Section of Cardiorespiratory Medicine, Department of Medicine, University of Cambridge, Victor Phillip Dahdaleh Heart and Lung Research Institute , Papworth Road, Cambridge CB2 0BB ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yee-Hung","family":"Chan","sequence":"additional","affiliation":[{"name":"Section of Cardiorespiratory Medicine, Department of Medicine, University of Cambridge, Victor Phillip Dahdaleh Heart and Lung Research Institute , Papworth Road, Cambridge CB2 0BB ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nichola","family":"Figg","sequence":"additional","affiliation":[{"name":"Section of Cardiorespiratory Medicine, Department of Medicine, University of Cambridge, Victor Phillip Dahdaleh Heart and Lung Research Institute , Papworth Road, Cambridge CB2 0BB ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Murray C H","family":"Clarke","sequence":"additional","affiliation":[{"name":"Section of Cardiorespiratory Medicine, Department of Medicine, University of Cambridge, Victor Phillip Dahdaleh Heart and Lung Research Institute , Papworth Road, Cambridge CB2 0BB ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin R","family":"Bennett","sequence":"additional","affiliation":[{"name":"Section of Cardiorespiratory Medicine, Department of Medicine, University of Cambridge, Victor Phillip Dahdaleh Heart and Lung Research Institute , Papworth Road, Cambridge CB2 0BB ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7909-2977","authenticated-orcid":false,"given":"Helle 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