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.
