Endothelial dysfunction in atherosclerosis: from classical pathways to emerging mechanisms

Abstract

Endothelial dysfunction is a pivotal factor in the pathogenesis of atherosclerosis, driving plaque formation, inflammation, and thrombosis. This review synthesizes classical mechanisms and emerging perspectives on endothelial dysfunction, emphasizing its role in atherogenesis. Traditional contributors, including lifestyle factors, lipid dysregulation, shear stress, and nitric oxide (NO) deficiency, are discussed alongside novel insights from single-cell RNA sequencing, metabolomics, and intercellular communication. scRNA-seq has unveiled endothelial cell (EC) heterogeneity and endothelial-to-mesenchymal transition (EndMT) as critical contributors to plaque instability. Metabolites such as trimethylamine N-oxide (TMAO) and homocysteine derivatives exacerbate endothelial injury, while gut microbiome interactions further modulate disease progression. Exosome-mediated crosstalk between ECs, immune cells, and vascular smooth muscle cells (VSMCs) highlights new pathways in vascular inflammation and remodeling. Current pharmacotherapies, such as lipid-lowering and anti-inflammatory drugs, improve endothelial function, and emerging strategies like nanotechnology and exosome-based therapies show promise as well. Integrating classical and novel approaches could enhance our understanding of endothelial biology and lead to targeted therapies, addressing atherosclerosis-related diseases.

Keywords

Endothelial dysfunction / atherosclerosis / nitric oxide / shear stress / single-cell RNA sequencing / exosomes / metabolites

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