{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T18:59:17Z","timestamp":1790189957677,"version":"4.1.0"},"reference-count":62,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"10","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["ATVB"],"published-print":{"date-parts":[[2026,10]]},"abstract":"<jats:sec>\n                    <jats:title>BACKGROUND:<\/jats:title>\n                    <jats:p>\n                      Comprehensive investigation of endothelial cell (EC) dysfunction during atherosclerosis with single-cell omics has resulted in the proposal that ECs undergo multiple alternative cell fate decisions during disease, but lack of lineage tracing or spatial localization complicates interpretation of these data.\n                      <jats:italic toggle=\"yes\">TWIST1<\/jats:italic>\n                      , a causal gene for multiple atherosclerotic vascular diseases, is activated with low shear stress in ECs, and EC-\n                      <jats:italic toggle=\"yes\">Twist1<\/jats:italic>\n                      knockout results in reduced atherosclerosis. However, it remains unclear how\n                      <jats:italic toggle=\"yes\">Twist1<\/jats:italic>\n                      affects EC phenotype and plaque biology.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS:<\/jats:title>\n                    <jats:p>\n                      We performed EC lineage tracing, in situ analysis, and scRNA-Seq (single-cell RNA-sequencing) in\n                      <jats:italic toggle=\"yes\">ApoE<\/jats:italic>\n                      <jats:sup>\n                        <jats:italic toggle=\"yes\">\u2212\/\u2212<\/jats:italic>\n                      <\/jats:sup>\n                      mice, both before disease and after 16 weeks of high-fat diet. We also performed these studies with 2 mouse models of EC\n                      <jats:italic toggle=\"yes\">Twist1<\/jats:italic>\n                      deletion. We overexpressed\n                      <jats:italic toggle=\"yes\">TWIST1<\/jats:italic>\n                      in human coronary artery ECs exposed to different flow conditions, followed by bulk RNA-seq. Human scRNA-Seq data were used to validate key findings in the mouse model.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS:<\/jats:title>\n                    <jats:p>\n                      We found that EC phenotypic modulation during atherosclerosis is characterized by both proinflammatory and endothelial-to-mesenchymal transition gene programs, occurring simultaneously along a single-cell fate transition. Human scRNA-Seq data validated a similar endothelial-to-mesenchymal transition during disease. We found that the commonly used\n                      <jats:italic toggle=\"yes\">Twist1<\/jats:italic>\n                      conditional allele is hypomorphic, leading to reduced\n                      <jats:italic toggle=\"yes\">Twist1<\/jats:italic>\n                      expression in multiple cell types. Using a mouse model of EC-specific\n                      <jats:italic toggle=\"yes\">Twist1<\/jats:italic>\n                      deletion, we found reduced EC phenotypic modulation, decreased lesion size, and a more stable lesion phenotype. Integration of\n                      <jats:italic toggle=\"yes\">TWIST1<\/jats:italic>\n                      overexpression in human coronary artery ECs with the mouse scRNA-seq data identified specific\n                      <jats:italic toggle=\"yes\">TWIST1<\/jats:italic>\n                      -induced targets including CXCL12 and E-selectin during EC phenotypic modulation.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSIONS:<\/jats:title>\n                    <jats:p>\n                      Our study revealed important aspects of EC phenotypic modulation during atherosclerosis, unifying disparate observations in the field. We identified key cellular and molecular mechanisms underlying a top risk locus for multiple vascular diseases, highlighting the promotion of inflammatory endothelial-to-mesenchymal transition by\n                      <jats:italic toggle=\"yes\">TWIST1<\/jats:italic>\n                      as a key driver of disease risk.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/atvbaha.126.324428","type":"journal-article","created":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T09:00:26Z","timestamp":1788426026000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":0,"title":["<i>Twist1<\/i>\n                    Promotes Endothelial Phenotypic Transition and Unstable Plaque Phenotype During Atherosclerosis"],"prefix":"10.1161","volume":"46","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9330-4761","authenticated-orcid":true,"given":"Danielle 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