{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T15:03:00Z","timestamp":1789052580535,"version":"build-2803163510"},"reference-count":56,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"5","license":[{"start":{"date-parts":[[2026,5,1]],"date-time":"2026-05-01T00:00:00Z","timestamp":1777593600000},"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":[[2026,5]]},"abstract":"<jats:sec>\n                    <jats:title>BACKGROUND:<\/jats:title>\n                    <jats:p>Thoracic aortic dissection (TAD) is a life-threatening acute vascular condition with high morbidity and mortality. Endothelial cells (ECs) are critical for maintaining vascular homeostasis, yet the role of endothelial-to-mesenchymal transition (EndoMT), a key cell-fate process in vascular development and disease, in TAD remains poorly defined. Furthermore, the functional role of PDK4 (pyruvate dehydrogenase kinase 4) as a driver of this pathological cell-fate transition has not been elucidated.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS:<\/jats:title>\n                    <jats:p>To delineate the mechanistic contribution of EndoMT to TAD, we integrated transcriptomic profiling and immunofluorescence analysis in human aortic specimens and a \u03b2-aminopropionitrile\u2013induced murine model. Following the identification of PDK4 as a critical downstream effector of EndoMT signaling via RNA-sequencing and chromatin immunoprecipitation assays, its functional role was validated using conditional EC-specific knockout mice and adeno-associated virus\u2013mediated endothelial gene modulation. Serum samples were collected, and ELISA was used to measure levels of endothelial injury markers for assessing EC-dysfunction. In addition, therapeutic potential was assessed using dichloroacetate, a small-molecule PDK4 inhibitor.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS:<\/jats:title>\n                    <jats:p>\n                      A robust activation of the EndoMT gene program was observed in both human TAD specimens and murine aortic tissues, characterized by the loss of endothelial identity and acquisition of mesenchymal traits. Transcriptomic screening pinpointed PDK4 as a critical mediator upregulated during EndoMT. Mechanistically, we demonstrated that the transcription factor\n                      <jats:italic toggle=\"yes\">SNAI1<\/jats:italic>\n                      directly binds to the\n                      <jats:italic toggle=\"yes\">PDK4<\/jats:italic>\n                      promoter to activate its expression. In turn, excessive PDK4 promotes EndoMT via lactate accumulation, establishing a PDK4-EndoMT positive feedback loop that sustains pathological remodeling in TAD. In vivo, EC-specific\n                      <jats:italic toggle=\"yes\">Pdk4<\/jats:italic>\n                      overexpression induced spontaneous aortic dissection and rupture. Conversely, EC-\n                      <jats:italic toggle=\"yes\">Pdk4<\/jats:italic>\n                      -knockdown or pharmacological inhibition with dichloroacetate attenuated TAD progression, preserved vascular integrity, and improved survival.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSIONS:<\/jats:title>\n                    <jats:p>Our findings demonstrate that the pathological EndoMT program is activated in ECs by PDK4, which aggravates TAD development in \u03b2-aminopropionitrile\u2013induced mouse models, highlighting PDK4 as a promising therapeutic target for TAD.<\/jats:p>\n                  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