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While several lines of evidences in human epidemiological and animal studies suggest chronic aerosol exposure accelerates atherosclerosis; the cellular and molecular mechanisms underlying this pathological remain unknown.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>\n                    We exposed hyperlipidemic mice to chronic e-cigarette aerosol inhalation and characterized the plaque cellular landscape by coupling SMC lineage tracing with single-cell transcriptomic\/epigenomic profiling and histologic phenotyping. We subsequently leveraged human coronary artery smooth muscle cells (HCASMCs) to validate\n                    <jats:italic>in vivo<\/jats:italic>\n                    discovery and identified E-cig specific pathological signaling pathways relevant to human vascular disease risk.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>\n                    Chronic E-cig aerosol exposure accelerated atherosclerosis, increasing both SMC phenotypic modulation and plaque macrophage burden in a lipid-independent manner. Transcriptomically, SMCs are particularly more sensitive to E-cig than other vascular cell types. E-cig exposure reprogrammed SMCs toward a pro-calcifying, chondrogenic phenotype, thereby enhancing vascular ossification\n                    <jats:italic>in vivo<\/jats:italic>\n                    and in HCASMCs\n                    <jats:italic>in vitro<\/jats:italic>\n                    . Mechanistically, E-cig mediated SMC fate alteration occurs through activation of a glutamatergic\/NMDAR signaling program, that increased NMDAR-dependent Ca\n                    <jats:sup>2+<\/jats:sup>\n                    influx in a\n                    <jats:italic>GRIN2A<\/jats:italic>\n                    dependent manner. Notably, inhibition of\n                    <jats:italic>GRIN2A<\/jats:italic>\n                    mediated signaling reversed E-cig-induced pathological shifts in SMC phenotype.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>\n                    SMC chondrogenic reprogramming and subsequent vascular calcification are central to the detrimental cardiovascular consequences of E-cig exposure. Our findings implicate a\n                    <jats:italic>GRIN2A<\/jats:italic>\n                    -dependent glutamatergic\/NMDAR signaling axis in SMC as a primary driver of this calcifying remodeling program. These findings define a SMC-specific vulnerability to E-cig aerosols and establish the\n                    <jats:italic>GRIN2A<\/jats:italic>\n                    \/NMDAR pathway as potential therapeutic targets for mitigating E-cig-associated cardiovascular disease.\n                  <\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2025.09.13.675958","type":"posted-content","created":{"date-parts":[[2025,9,18]],"date-time":"2025-09-18T00:05:41Z","timestamp":1758153941000},"source":"Crossref","is-referenced-by-count":0,"title":["Chronic Electronic Cigarette Exposure Promotes Atherosclerosis and Chondrogenic Modulation of Smooth Muscle Cells"],"prefix":"10.64898","author":[{"given":"Isabella","family":"Damiani","sequence":"first","affiliation":[{"name":"Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA 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