Hypercholesterolemia-induced LXR Signaling in Smooth Muscle Cells (SMCs) Contributes to Atherosclerotic Lesion Remodeling and Regulates Vascular and Visceral SMC Function

ABSTRACT: BACKGROUND: Vascular smooth muscle cells (VSMC) are the most abundant cell type in the artery’s media layer and regulate vascular tone and lesion remodeling during atherogenesis. Like monocyte-derived macrophages, VSMCs accumulate excess lipids and contribute to the total intimal foam cell population in human coronary plaque and mouse aortic atheroma. While there are extensive studies characterizing the contribution of lipid metabolism in macrophage immunometabolic responses in atherosclerotic plaques, the role of VSMC lipid metabolism in regulating vascular function and lesion remodeling in vivo remains poorly understood. METHODS: We re-analyzed publicly available single-cell RNA sequencing (scRNA-seq) data from mouse atherosclerosis studies and found Liver X receptor (LXR) signaling in VSMCs was continuously activated during atherogenesis. We thus generated mice with an inducible SMC-specific knockout of LXR/LXR on a fate mapping background by crossbreeding LXRf/fLXRf/f mice with Myh11-CreERT2;mTmGf/f mice. Mice were administered with tamoxifen (1 mg/day) for 10 consecutive days and followed by a 2-week resting period to induce CreERT2 mediated recombination. To induce hypercholesterolemia and atherosclerosis, we injected Myh11-CreERT2;mT/mGf/f;LXRf/fLXRf/f mice and Myh11-CreERT2;mT/mGf/f mice with AAV8-PCSK9 and fed them with a Western diet (WD) for 16 weeks. Metabolic, immunocytochemistry and genomic analysis were conducted to assess lesion size and morphology and unravel the molecular mechanism by which LXR in VSMC contributes to lesion formation. RESULTS: 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 transitional cells. This phenotypic switching is accompanied with reduced index of plaque stability characterized by larger necrotic core area and reduced fibrous cap thickness. Moreover, SMC-specific LXR deficiency impaired vascular function and caused visceral myopathy characterized by bladder maladaptive remodeling and gut lipid malabsorption. CONCLUSIONS: We unveil an essential role of hypercholesterolemia-induced LXR signaling in atherosclerotic lesion remodeling, controlling the fate decision of VSMCs and regulating vascular and visceral SMCs functions.

ORGANISM(S): Mus musculus

PROVIDER: GSE269449 | GEO | 2025/03/03

REPOSITORIES: GEO