Atherosclerosis: Insights into Vascular Pathobiology and Outlook to Novel Treatments.

ABSTRACT

The pathobiology of atherosclerosis and its current and potential future treatments are summarized, with a spotlight on three central cell types involved (i) endothelial cells (ECs), (ii) macrophages, and (iii) vascular smooth muscle cells (VSMCs). (i) EC behaviour is regulated by the central transcription factors YAP/TAZ in reaction to biomechanical forces, such as hemodynamic shear stress. (ii) VSMC transdifferentiation (phenotype switching) to a macrophage-like phenotype contributes to the majority of cells positive for common cell surface macrophage markers in atherosclerotic plaques. (iii) Intra-plaque macrophages originate in a significant number from vascular resident macrophages. They can be activated via pattern recognition receptors on cell membrane (e.g. toll-like receptors) and inside cells (e.g. inflammasomes), requiring priming by neutrophil extracellular traps (NETs). ECs and macrophages can also be characterized by single-cell RNA sequencing. Adaptive immunity plays an important role in the inflammatory process. Future therapeutic options include vaccination, TRAF-STOPs, senolysis, or CD47 blockade. Graphical Abstract.