Jung, I.-H. | Search bioRxiv

bioRxiv2025

Targeting Modulated Vascular Smooth Muscle Cells in Atherosclerosis via FAP-Directed Immunotherapy

Vascular smooth muscle cell (VSMC) and immune cell diversification play a central role in driving atherosclerotic coronary artery disease (CAD)1-3. However, the molecular mechanisms governing cell state transitions within the neo-intima in human CAD remain poorly understood, and no lipid-independent therapies are currently approved for its treatment. Here, we performed multi-omic single-cell gene expression profiling, epitope mapping, and spatial transcriptomics from 27 human coronary arteries. Our analysis identified fibroblast activation protein (FAP) as a marker of modulated VSMCs within the neo-intima. Genetic lineage tracing in mice confirmed that FAP cells in the plaque originate from medial VSMCs. Additionally, non-invasive positron emission tomography (PET) imaging in patients with CAD revealed focal FAP uptake in atherosclerotic lesions. Spatial transcriptomics further delineated the distinct localization of VSMC and immune cell subsets within plaques, with FAP states enriched in the neo-intima. To explore the therapeutic potential of targeting de-differentiated VSMCs, we developed an anti-FAP bispecific T-cell engager (BiTE) and demonstrated that it significantly reduced the plaque burden in multiple mouse models of atherosclerosis. Collectively, our study provides the first single-cell and spatially resolved map of human CAD, establishes FAP as a marker of modulated smooth muscle cells, and demonstrates the broader potential of immunotherapeutics for lipid independent targets in atherosclerotic CAD.

genomics↗

bioRxiv2020

SVEP1, a novel human coronary artery disease locus, promotes atherosclerosis

A low-frequency variant of SVEP1, an extracellular matrix protein, is associated with risk of coronary disease in humans independent of plasma lipids. Despite a robust statistical association, however, it was unclear if and how SVEP1 might contribute to atherosclerosis. Here, using Mendelian randomization and complementary mouse models, we provide evidence that SVEP1 promotes atherosclerosis in humans and mice. We find that SVEP1 is expressed by vascular smooth muscle cells (VSMCs) within the atherosclerotic plaque. VSMCs also interact with SVEP1, causing proliferation and dysregulation of key differentiation pathways, including integrin and Notch signaling. Fibroblast growth factor receptor transcription increases in VSMCs interacting with SVEP1, and is further increased by the coronary disease-associated SVEP1 variant. These effects ultimately drive inflammation and promote atherosclerosis. Taken together, our results suggest that VSMC-derived SVEP1 is a pro-atherogenic factor, and support the concept that pharmacological inhibition of SVEP1 should protect against atherosclerosis in humans.

genetics↗