Flow-induced reprogramming of endothelial cells in atherosclerosis

Abstract

Atherosclerotic diseases such as myocardial infarction, ischaemic stroke and peripheral artery disease continue to be leading causes of death worldwide despite the success of treatments with cholesterol-lowering drugs and drug-eluting stents, raising the need to identify additional therapeutic targets. Interestingly, atherosclerosis preferentially develops in curved and branching arterial regions, where endothelial cells are exposed to disturbed blood flow with characteristic low-magnitude oscillatory shear stress. By contrast, straight arterial regions exposed to stable flow, which is associated with high-magnitude, unidirectional shear stress, are relatively well protected from the disease through shear-dependent, atheroprotective endothelial cell responses. Flow potently regulates structural, functional, transcriptomic, epigenomic and metabolic changes in endothelial cells through mechanosensors and mechanosignal transduction pathways. A study using single-cell RNA sequencing and chromatin accessibility analysis in a mouse model of flow-induced atherosclerosis demonstrated that disturbed flow reprogrammes arterial endothelial cells in situ from healthy phenotypes to diseased ones characterized by endothelial inflammation, endothelial-to-mesenchymal transition, endothelial-to-immune cell-like transition and metabolic changes. In this Review, we discuss this emerging concept of disturbed-flow-induced reprogramming of endothelial cells (FIRE) as a potential pro-atherogenic mechanism. Defining the flow-induced mechanisms through which endothelial cells are reprogrammed to promote atherosclerosis is a crucial area of research that could lead to the identification of novel therapeutic targets to combat the high prevalence of atherosclerotic disease.

Nonpreferential but Detrimental Accumulation of Macrophages With Clonal Hematopoiesis-Driver Mutations in Cardiovascular Tissues—Brief Report

“…These distinctions could result from the tissue type where macrophages adapt to their local environment or the general disease context. The formation of carotid artery plaques involves excessive lipid deposition, endothelial damage, and inflammatory immunocyte infiltration at the lesions, [32][33][34] while heart diseases encompass malfunctioning cardiomyocytes, fibroblasts, and imbalanced immune activities in response to intrinsic or extrinsic (eg, ischemia, valvular defects) triggers. [35][36][37] Overall, our data manifest that the DNMT3A and TET2 mutations associate with inflammatory macrophages in both cardiovascular tissues.…”

NF-κB in biology and targeted therapy: new insights and translational implications

“…Furthermore, disturbed flow-induced ECs dysfunction through mechanotransduction pathways result in the activation of NF-κB signaling. 397 Vascular smooth muscle cells (VSMCs) are the primary source of plaque cells. 398 The major pathogenic mechanism underlying the formation of atherosclerotic plaques was believed to be the phenotypic switching of VSMCs from contractile to proliferative synthetic types in response to arterial inflammation.…”

Single-Cell Transcriptomic Profiling Unveils Critical Metabolic Alterations and Signatures in Progression of Atherosclerosis

“…Atherosclerosis is characterized by lipid deposition, calcification, and angiogenesis within plaques [5]. Recent investigations propose that the metabolic reprogramming of glucose, cholesterol, fatty acid, and amino acid in cells such as macrophages, endothelial cells (ECs), and vascular smooth muscle cells (VSMCs) significantly contributes to inflammation at all stages of atherosclerosis, from lesion initiation to advanced stages, and even to lesion regression [6][7][8][9]. For example, disruptions in glycolysis, along with the accumulation of its metabolite lactic acid, was reported to regulate endothelial inflammation and the formation of plaques [10].…”