Abstract Body: Atherosclerotic cardiovascular disease (CVD) is the leading cause of mortality worldwide. Smooth muscle cells (SMCs) make up the bulk of the healthy arterial wall and atherosclerotic lesions, and can undergo modulation (dedifferentiation, migration, and transdifferentiation into various SMC-derived cell types (SDCs)) during atherosclerotic progression. The mechanisms modulating SMC phenotype switching and the functions of the SDCs produced are not fully elucidated. The unfolded protein response (UPR) has been implicated in SMC modulation and linked to plaque instability and rupture. We hypothesized that disruption of the Perk UPR pathway in SMCs could partially inhibit SMC modulation in lesions and improve features of lesion stability in mouse atherogenic models. In this study, we used an SMC lineage-traced, SMC-specific inducible Perk KO atherogenic mouse, to determine the effects of SMC-specific Perk depletion on atherosclerotic SDCs and lesion stability via scRNA-seq and by histological scoring of lesion content. ScRNA-seq analysis did not reveal any significant changes in SDC populations following tamoxifen-induced deletion of Perk in SMCs in 8 week old mice, and no significant changes were detected in lesion size, fibrotic cap thickness, or macrophage content in developed lesions after 16 weeks of western diet, suggesting no effect of SMC-specific Perk UPR silencing on lesion stability or SMC modulation.