Smooth muscle cell-derived cell fates and cellular interactions in atherosclerotic plaque stability in disease progression and regression.

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Residual cardiovascular disease (CVD) risk in patients on lipid lowering therapy is a major unmet clinical need. Our goal is to investigate mechanisms of plaque stabilization and destabilization focused on functions of vascular smooth muscle cell (SMC) derived cells (SDCs), and their crosstalk with macrophages (Mϕ), in mouse models and human CVD. We focus on SDC types, location and functions and their interactions with Mϕ in plaque stability in disease progression and regression. SMCs can transition through an intermediate state into atheroprotective, e.g., fibrochondrocyte (SMC-FbC), or atherogenic, e.g., SMC-derived macrophage-like (SMC-Mϕ) identities. Master regulators of SDC identities are emerging for protective (retinoic acid, Tcf21) and harmful (Klf4) types, but mechanisms are poorly understood. We hypothesize that SDC functions in lesion stability and clinical CVD are malleable and can be inferred from spatial and single-cell (sc) omics; SMC-Mϕ are inflammatory and activate bystander Mϕ to promote plaque instability; oxidative DNA (ox-DNA) damage regulates SDC identities and functions to destabilize lesions; and crosstalk of atherogenic SDCs and Mϕs promotes lesion instability and impairs regression. Aim 1 will determine locations and functions of SDC types in atherosclerosis progression and test if SMC-Mϕ and SDC ox-DNA damage drive atherogenic SMC identities and lesion instability while Aim 2 will address whether some SDCs promote and others curb plaque stabilization in atherosclerosis regression, and if regression is attenuated by SMC-Mϕ and SDC ox-DNA damage. In these Aims, we will; (1) integrate spatial hybridization-based RNA in situ sequencing (HybRISS), sc-omics and SMC lineage tracing to define identity, spatial functions, and master regulators of SDCs during lesion progression and regression, focusing on functions such as SMC-Mϕs inflammasome and impaired efferocytosis; (2) use a diphtheria toxin (Dtx) mouse model to track SMC-Mϕ and to test if depletion of SMC-Mϕ reduces lesion instability in progression and accelerates resolution; and (3) use an SMC-inducible 8-oxoguanine DNA glycosylase (OGG1) transgenic mouse model to test if SMC ox-DNA damage, which is increased in atherosclerosis, pushes SDCs to atherogenic identities. Aim 3 will test if specific SDC types and their regulatory genes promote clinical CVD. Using multi-omic data from the Munich Vascular Biobank, we will deploy an integrated strategy to go from descriptive studies in human plaques, to regulatory genetic variation in SDCs, to testing causal relationship of these variants with clinical CVD in large genetic data. Our work will provide mechanistic insight into the role of SDC types, their spatial functions, and crosstalk with Mϕ to achieve our overall goal of greater mechanistic understanding of factors affecting atherosclerotic plaque stability and instability. Human translation will establish clinical relevance, causality and context for new treatment strategies for CVD.