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Twist1 promotes endothelial phenotypic transition and unstable plaque phenotype during atherosclerosis

ABSTRACT: Background: Comprehensive investigation of endothelial cell (EC) dysfunction during atherosclerosis with single-cell ‘omics’ has resulted in the proposal that ECs undergo multiple alternative cell fate decisions during disease, but lack of lineage tracing and/or spatial localization complicates interpretation of these data. TWIST1, a causal gene for multiple atherosclerotic vascular diseases, is activated with low shear stress in endothelial cells (ECs), and EC-Twist1 knockout results in reduced atherosclerosis. However, it remains unclear how Twist1 affects EC phenotype and plaque biology. Methods: We performed EC lineage tracing, in situ analysis and scRNA-Seq in ApoE-/- mice, both prior to disease and after 16 weeks of high-fat diet. We also performed these studies with two mouse models of EC Twist1 deletion. We overexpressed TWIST1 in human coronary artery endothelial cells (HCAECs) exposed to different flow conditions, followed by bulk RNAseq. Human scRNA-Seq data were used to validate key findings in the mouse model. Results: We found that EC phenotypic modulation during atherosclerosis is characterized by both pro-inflammatory and EndMT gene programs, occurring simultaneously along a single cell fate transition. Human scRNA-Seq data validated a similar EndMT transition during disease. We found that the commonly-used Twist1 conditional allele is hypomorphic, leading to reduced Twist1 expression in multiple cell types. Using a mouse model of EC-specific Twist1 deletion, we found reduced EC phenotypic modulation, decreased lesion size, and a more stable lesion phenotype. Integration of TWIST1 overexpression in HCAECs with the mouse scRNAseq data identified specific TWIST1-induced targets including CXCL12 and E-selectin during EC phenotypic modulation. Conclusions: Our study revealed important aspects of EC phenotypic modulation during atherosclerosis, unifying disparate observations in the field. We identified key cellular and molecular mechanisms underlying a top risk locus for multiple vascular diseases, highlighting the promotion of inflammatory EndMT by TWIST1 as a key driver of disease risk.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE342905 | GEO | 2026/09/10

REPOSITORIES: GEO

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Project description:Background: Phenotypic plasticity of smooth muscle cells (SMCs) and endothelial cells (ECs) contributes to atherosclerotic plaque composition and stability, yet how shifts in one population influence the contribution and function of the other under conditions of vascular stress, such as irradiation, is poorly understood. A major limitation has been the inability to simultaneously fate map both cell types within the same lesion, with most studies mapping one lineage while inferring the other using unreliable dynamically changing marker genes, risking false-positive and false negative assignment. Methods: We generated dual lineage-tracing Apoe-deficient mice, enabling simultaneous fate mapping of SMCs and ECs. This model was used to extend prior findings from single lineage tracing models demonstrating irradiation-induced loss of SMC lesion investment and expansion of EC-derived cells. Dual lineage-tracing mice were subjected to irradiation followed by Western diet feeding to induce atherosclerosis. Lineage tracing, immunostaining and scRNA-seq analysis were used to define coordinated SMC and EC responses and identify changes relevant to plaque instability. Results: Dual lineage tracing simultaneously labeled SMC- and EC-derived cells in healthy and atherosclerotic vessels. Irradiation induced divergent responses: SMC-derived cells failed to invest in lesions and upregulated stress-activated inflammatory genes, whereas EC-derived cells expanded and upregulated SMC-associated genes. However, EC-derived cells within lesions failed to induce extracellular matrix genes, and lesions from irradiated mice exhibited reduced collagen content and fewer ACTA2+ cells within the fibrous cap, consistent with reduced plaque stability. Conclusions: Dual lineage-tracing of SMCs and ECs demonstrated that irradiation-induced loss of lesional SMC and expansion of EC-derived ACTA2+ cells are not artifacts of false lineage assignment. By resolving SMC and EC fate within the same lesion, we identify irradiation-induced cell dynamics including inflammatory reprogramming of SMCs, EC phenotypic modulation, impaired extracellular matrix organization, and reduced ACTA2⁺ fibrous cap cellularity that may contribute to radiotherapy-associated increased atherosclerotic cardiovascular disease risk. Key Words: Atherosclerosis; smooth muscle cells; endothelial cells; lineage tracing; radiation; extracellular matrix; cellular plasticity

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Twist1 promotes endothelial phenotypic transition and unstable plaque phenotype during atherosclerosis

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