{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T07:06:11Z","timestamp":1790233571220,"version":"4.1.0"},"reference-count":53,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"8","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["ATVB"],"published-print":{"date-parts":[[2026,8]]},"abstract":"<jats:sec>\n                    <jats:title>BACKGROUND:<\/jats:title>\n                    <jats:p>Ischemic stroke remains a leading contributor to cardiovascular disease, and unstable atherosclerotic plaques in the carotid arteries are an important contributor to its pathogenesis. Notably, sex differences exist in plaque composition and morphology; whereas males are more likely to develop unstable plaques, females present with worse outcomes poststroke. As such, this study aims to elucidate sex-specific cellular and molecular mechanisms driving carotid plaque instability.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS:<\/jats:title>\n                    <jats:p>We performed single-cell RNA sequencing on carotid endarterectomy specimens from male and female patients with stable or unstable plaques, profiling over 64\u2009000 cells. To spatially contextualize these findings, we integrated single-cell RNA sequencing data with CosMx high-plex spatial transcriptomics using the human discovery 6k RNA panel to map gene expression and cell type localization within key histological regions defining instability.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS:<\/jats:title>\n                    <jats:p>Single-cell RNA sequencing revealed that vascular smooth muscle cells (VSMCs), T lymphocytes, and macrophages comprised \u224888% of plaque-resident cells, with distinct sex-specific differences in relation to instability. In males, unstable plaques showed depletion of contractile VSMCs and an abundance of inflammatory synthetic and macrophage-like VSMCs, alongside increased inflammatory macrophages and activated naive T lymphocytes. In contrast, female unstable plaques retained relatively more contractile VSMCs but exhibited greater expansion of cytotoxic T lymphocytes and foam-cell macrophages. Sex-specific cell-cell interaction analysis demonstrated increased VSMC-to-stromal interactions and elevated macrophage-macrophage signaling in male and female unstable plaques, respectively. Through spatial transcriptomics, inflammatory synthetic VSMCs identified by single-cell RNA sequencing dominated the lipid core in both male and female unstable plaques. However, only in males did these cells also replace the fibrotic cap, forming immune-rich niches among themselves and with macrophage-like VSMCs.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSIONS:<\/jats:title>\n                    <jats:p>Overall, these findings uncover distinct cellular and spatial mechanisms driving plaque destabilization in males and females, highlighting the need for sex-specific approaches to the diagnosis and treatment of carotid atherosclerosis.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/atvbaha.125.323505","type":"journal-article","created":{"date-parts":[[2026,5,21]],"date-time":"2026-05-21T09:00:18Z","timestamp":1779354018000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":4,"title":["Single-Cell Spatial Transcriptomics Reveals Sex-Specific Differences Driving Carotid Atherosclerotic Plaque Instability"],"prefix":"10.1161","volume":"46","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1231-511X","authenticated-orcid":true,"given":"Jae Hyun","family":"Byun","sequence":"first","affiliation":[{"name":"Vascular Health Unit, Research Institute of the McGill University Health Centre (RI-MUHC), Department of Medicine, Faculty of Medicine, McGill University, Glen Site, Montreal, Qu\u00e9bec, Canada (J.H.B., H.P.Q., K.G., I.G., H.Z., S.S.D.)."},{"name":"Division of Clinical and Translational Research, Department of Medicine, Faculty of Medicine (J.H.B., S.S.D.), McGill University, Montreal, Qu\u00e9bec, Canada."},{"name":"Department of Medicine (J.H.B., H.P.Q., K.G., I.G., H.Z., S.S.D.), McGill University, Montreal, Qu\u00e9bec, Canada."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4240-4973","authenticated-orcid":true,"given":"Helena","family":"Papacostas Quintanilla","sequence":"additional","affiliation":[{"name":"Vascular Health Unit, Research Institute of the McGill University Health Centre (RI-MUHC), Department of Medicine, Faculty of Medicine, McGill University, Glen Site, Montreal, Qu\u00e9bec, Canada (J.H.B., H.P.Q., K.G., I.G., H.Z., S.S.D.)."},{"name":"Department of Medicine (J.H.B., H.P.Q., K.G., I.G., H.Z., S.S.D.), McGill University, Montreal, Qu\u00e9bec, Canada."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karina","family":"Gasbarrino","sequence":"additional","affiliation":[{"name":"Vascular Health Unit, Research Institute of the McGill University Health Centre (RI-MUHC), Department of Medicine, Faculty of Medicine, McGill University, Glen Site, Montreal, Qu\u00e9bec, Canada (J.H.B., H.P.Q., K.G., I.G., H.Z., S.S.D.)."},{"name":"Department of Medicine (J.H.B., H.P.Q., K.G., I.G., H.Z., S.S.D.), McGill University, Montreal, Qu\u00e9bec, Canada."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ioanna","family":"Gianopoulos","sequence":"additional","affiliation":[{"name":"Vascular Health Unit, Research Institute of the McGill University Health Centre (RI-MUHC), Department of Medicine, Faculty of Medicine, McGill University, Glen Site, Montreal, Qu\u00e9bec, Canada (J.H.B., H.P.Q., K.G., I.G., H.Z., S.S.D.)."},{"name":"Department of Medicine (J.H.B., H.P.Q., K.G., I.G., H.Z., S.S.D.), McGill University, Montreal, Qu\u00e9bec, Canada."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9050-9315","authenticated-orcid":true,"given":"Ashot S.","family":"Harutyunyan","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Victor Phillip Dahdaleh Institute of Genomic Medicine (A.S.H., S.O., J.R.), McGill University, Montreal, Qu\u00e9bec, Canada."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Spyros","family":"Oikonomopoulos","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Victor Phillip Dahdaleh Institute of Genomic Medicine (A.S.H., S.O., J.R.), McGill University, Montreal, Qu\u00e9bec, Canada."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John P.","family":"Veinot","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, University of Ottawa, Ontario, Canada (J.P.V.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huaien","family":"Zheng","sequence":"additional","affiliation":[{"name":"Vascular Health Unit, Research Institute of the McGill University Health Centre (RI-MUHC), Department of Medicine, Faculty of Medicine, McGill University, Glen Site, Montreal, Qu\u00e9bec, Canada (J.H.B., H.P.Q., K.G., I.G., H.Z., S.S.D.)."},{"name":"Department of Medicine (J.H.B., H.P.Q., K.G., I.G., H.Z., 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