Abstract 129: Hypercholesterolemia-induced Lxr Signaling In Smc Contributes To Atherosclerotic Lesion Remodeling And Regulates Vascular And Visceral Smc Function

Vascular smooth muscle cells (VSMCs) play an important role during atherogenesis, regulating vasotone and lesion remodeling. Recent advances in combing VSMC lineage tracing and scRNA-seq have generated high-dimensional analysis of VSMC profiles of atherosclerotic lesion, delineating multiple VSMC-derived transitional states in vascular lesions, which can further adopt plaque stabilizing or plaque destabilizing cell states. Despite the identification of several transcription factors that govern SMC fate, the signaling events that promote SMC transitional state remain poorly understood. Our trajectory analysis of VSMCs gene expression reveals the activation of liver X receptor (LXR) signaling, a master regulator of lipid metabolism, during the progression of atherosclerosis, suggesting a relevant role of this transcription factor in controlling VSMC fate decision and lesion remodeling. To dissect the specific contribution of LXR signaling in VSMC during atherogenesis, we generated and characterized mice in which the LXRα and β genes were conditionally ablated in SMCs in the adult vasculature and visceral tissues. Deficiency of LXR in SMCs under hypercholesterolemic condition influenced lesion remodeling by altering the fate of de-differentiated SMC and promoting the accumulation of VSMC-derived transition cells. This phenotypic switching is accompanied with increased features of plaque instability characterized by larger necrotic cores and reduced fibrous cap thickness. Moreover, LXR SMC deficiency impaired vascular function and caused visceral myopathy characterized by bladder maladaptive remodeling and altered gut lipid absorption. Together, we uncovered an essential role of LXR-regulated signaling that contributes to atherosclerotic lesion remodeling, and vascular/ visceral SMC function.