Multiple cell types contribute to the atherosclerotic lesion fibrous cap by PDGFRβ and bioenergetic mechanisms

Abstract

Stable atherosclerotic plaques are characterized by a thick extracellular matrix (ECM)-rich fibrous cap populated by protective ACTA2 + myofibroblast (MF)-like cells, assumed to be almost exclusively derived from smooth muscle cells (SMC). Herein, we show that in murine and human lesions, 20 to 40% of ACTA2 + fibrous caps cells, respectively, are derived from non-SMC sources, including endothelial cells (EC) or macrophages that have undergone Endothelial-to-Mesenchymal (EndoMT) or Macrophage-to-Mesenchymal (MMT) transitions. In addition, we show that SMC-specific knockout of the platelet derived growth factor receptor beta (PDGFRB) in Apoe −/− mice fed a Western diet (WD) for 18 weeks resulted in brachiocephalic artery (BCA) lesions nearly devoid of SMC but with no changes in lesion size, remodeling, or indices of stability including percent of ACTA2 + fibrous cap cells. However, prolonged WD feeding of SMC-PDGFRB knockout mice resulted in reduced indices of stability, indicating that EndoMT and MMT-derived MFs cannot compensate indefinitely for loss of SMC-derived MFs. Using single cell and bulk RNA-seq analyses of the BCA region and in vitro models, we provide evidence that SMC to MF transitions (SMC-MFT) are induced by PDGF and TFGβ and dependent on aerobic glycolysis, while EndoMT is induced by IL1β and TGFβ. Together, we provide evidence that the ACTA2 + fibrous cap originates from a tapestry of cell types, which transition to an MF state through distinct signaling pathways that are either dependent on or associated with extensive metabolic reprogramming.

Dysfunctional Vascular Endothelium as a Driver of Atherosclerosis: Emerging Insights Into Pathogenesis and Treatment

“…The metastable nature of EndMT may be further elucidated with next-generation technologies that profile the atherosclerotic plaque and neighboring regions at the single-cell level, as recently used in studies of disturbed flow and endothelial reprogramming ( Andueza et al, 2020 ) and diabetic atherogenesis ( Zhao et al, 2021 ), as well as through the incorporation of computational models that predict endothelial activation and EndMT in various genetic and environmental conditions ( Weinstein et al, 2020 ). Second, although augmentation of EndMT has previously been associated with increased plaque progression ( Chen et al, 2015 ), emerging studies have highlighted a potential protective role of EndMT by maintaining plaque stability in the absence of SMC-derived myofibroblast-like cells ( Evrard et al, 2016 ; Newman et al, 2021 ). Evidently, a more nuanced understanding of EndMT in the context of plaque development and rupture is required before therapeutic inhibition of EndMT is considered for the treatment of atherosclerotic CVD.…”

Transcriptomic-based clustering of advanced atherosclerotic plaques identifies subgroups of plaques with differential underlying biology that associate with clinical presentation

“…Notably, the PDGF subunit B (p=0.005) showed the highest plasma levels in patients from plaque type #0. This growth factor is a potent activator of proliferation in cells of mesenchymal origin, and its receptor was recently shown to induce SMC-to- myofibroblast transitions in an aerobic glycolysis-dependent manner 19 (Fig 5b). Another marker SLAMF7 showed the highest plasma levels in patients with plaque type #2.…”

“…The role of metabolic pathways such as glycolysis 38 , fatty acid oxidation, and tryptophan catabolism may point to phenotype switching of vascular cells 19 . The differentiation of a contractile to a synthetic myofibriblast-like phenotype in smooth muscle cells is driven by switching from oxidative to glycolytic metabolism 39 .…”

Mural Cells: Potential Therapeutic Targets to Bridge Cardiovascular Disease and Neurodegeneration

“…The importance of non-VSMC plasticity (such as macrophage to mesenchymal transition (MMT) and endothelial to mesenchymal transition (EndoMT)) is the subject of recent growing research. For example, Newman et al discuss the contribution and potential atheroprotective roles of EndoMT and MMT to fibrous cap ACTA2 + cells [35,36]. However, for the purposes of this review, we will solely discuss the plasticity of VSMCs.…”