Handb Exp Pharmacol. 2026 Jun 19. doi: 10.1007/164_2026_814. Online ahead of print.
ABSTRACT
Atherosclerosis, the leading cause of cardiovascular death worldwide, is initiated by endothelial cells (ECs) dysfunction and sustained by maladaptive vascular remodeling. Far from being a uniform barrier, the endothelium is highly heterogeneous and phenotypically plastic. A central manifestation of this plasticity is endothelial-to-mesenchymal transition (EndMT), a dynamic continuum in which ECs progressively lose their endothelial identity and acquire mesenchymal, pro-fibrotic traits that contribute to every stage of atherosclerotic lesion development. This chapter reviews how atherogenic cues, including disturbed blood flow, oxidative stress, inflammation, and extracellular matrix stiffening, trigger EndMT, and how convergent signaling networks, notably TGF-β, together with Wnt/β-catenin, Notch, NF-κB/STAT3, and epigenetic regulators such as HDAC9, drive this process. These pathways are counterbalanced by protective mechanisms, including FGF and KLF2/KLF4 signaling, which help maintain endothelial homeostasis. We summarize evidence from in situ co-staining, genetic lineage tracing, epigenetic fate mapping, and single-cell multi-omics approaches, which collectively reveal distinct disease-associated EC subpopulations. We also review the in vitro, organ-on-a-chip, and murine models used to dissect EC plasticity. Finally, we discuss therapeutic and precision medicine strategies aimed at selectively reprogramming pathogenic endothelial states to promote plaque stabilization while preserving vascular integrity.
PMID:42313121 | DOI:10.1007/164_2026_814