bioRxiv : the preprint server for biology · 2026
Chronic Electronic Cigarette Exposure Promotes Atherosclerosis and Chondrogenic Modulation of Smooth Muscle Cells.
СтатьяПрепринтНазвание и аннотация: Перевод в очереди
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Damiani Isabella, Weldy Chad C, Zhao Quanyi, Solberg Elena Hurtado, Qin Guyu Tracy, Easwaran Meena, Zheng Siwen, Basu Sugandha, Gu Wenduo, Worssam Matthew, Monteiro Joao Pinho, Li Daniel Yuhang, Bahia Gurmenjit Kaur, Kundu Ramendra, Nguyen Trieu, Direnzo Elizabeth, Cheng Paul, Kim Juyong Brian
Аннотация
BACKGROUND: Electronic cigarette (E-cig) use has reached epidemic proportions worldwide, yet its cardiovascular consequences remain poorly defined. 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.
METHODS: 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 in vivo discovery and identified E-cig specific pathological signaling pathways relevant to human vascular disease risk.
RESULTS: 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 in vivo and in HCASMCs in vitro. Mechanistically, E-cig mediated SMC fate alteration occurs through activation of a glutamatergic/NMDAR signaling program, that increased NMDAR-dependent Ca2+ influx in a GRIN2A dependent manner. Notably, inhibition of GRIN2A mediated signaling reversed E-cig-induced pathological shifts in SMC phenotype.
CONCLUSIONS: SMC chondrogenic reprogramming and subsequent vascular calcification are central to the detrimental cardiovascular consequences of E-cig exposure. Our findings implicate a GRIN2A-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 GRIN2A/NMDAR pathway as potential therapeutic targets for mitigating E-cig-associated cardiovascular disease.
METHODS: 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 in vivo discovery and identified E-cig specific pathological signaling pathways relevant to human vascular disease risk.
RESULTS: 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 in vivo and in HCASMCs in vitro. Mechanistically, E-cig mediated SMC fate alteration occurs through activation of a glutamatergic/NMDAR signaling program, that increased NMDAR-dependent Ca2+ influx in a GRIN2A dependent manner. Notably, inhibition of GRIN2A mediated signaling reversed E-cig-induced pathological shifts in SMC phenotype.
CONCLUSIONS: SMC chondrogenic reprogramming and subsequent vascular calcification are central to the detrimental cardiovascular consequences of E-cig exposure. Our findings implicate a GRIN2A-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 GRIN2A/NMDAR pathway as potential therapeutic targets for mitigating E-cig-associated cardiovascular disease.