Atherosclerosis: Insights into Vascular Pathobiology and Outlook to Novel Treatments
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REVIEW
Atherosclerosis: Insights into Vascular Pathobiology and Outlook to Novel Treatments Marc P. Wolf 1
&
Patrick Hunziker 1,2
Received: 8 October 2019 / Accepted: 22 January 2020 # Springer Science+Business Media, LLC, part of Springer Nature 2020
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. Keywords Atherosclerosis . Endothelial cells . Macrophages . Tissue-resident macrophages . Vascular smooth muscle cells
Introduction Atherosclerosis is the leading cause of mortality globally [1, 2]. It entails acute myocardial infarction or ischaemic stroke. Many patients that present with first symptoms already have an underlying severe atherosclerosis, which means that besides prevention, reversal of the disease process is paramount. The disease relies on a chronic inflammatory process, involving vascular and immune cells [3]. This review summarizes recent findings of pathobiology and current and potential future treatment options. It may be of interest to the clinician thereby stimulating innovative clinical research projects. Associate Editor Nicola Smart oversaw the review of this article * Marc P. Wolf [email protected] 1
Nanomedicine Research Lab CLINAM, University Hospital Basel, University of Basel, Bernoullistrasse 20, CH-4056 Basel, Switzerland
2
CLINAM Foundation for Clinical Nanomedicine, Alemannengasse 12, CH-4016 Basel, Switzerland
Endothelial Cells: Shear Stress and Mechanosensing As cellular lining exposed to blood flow, endothelial cells react sensibly to minute changes in hemodynamic flow. Such mechanosensing is also important in other biological processes, e.g. organ development and cellular differentiation [4–7], where biomechanical forces can have profound effects on a cell phenotype to an extent of survival or death [8]. Fluidmechanical forces, induced by blood flow are sensed by a variety of mechanosensors on and in endothelial cells (ECs) [9, 10]. Mechanosensors on ECs include integrins and their assembly in foca
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