Endothelial Cell Phenotypic Plasticity in Atherosclerosis.

Area of Science:

• Vascular Biology
• Cellular Plasticity
• Cardiovascular Disease Pathogenesis

Background:

• Atherosclerosis, a major cause of death, begins with endothelial cell (EC) dysfunction and vascular remodeling.
• The endothelium exhibits heterogeneity and plasticity, with endothelial-to-mesenchymal transition (EndMT) being a key process.
• EndMT involves ECs losing identity and gaining pro-fibrotic traits, contributing to atherosclerotic lesion development.

Purpose of the Study:

• To review how atherogenic factors trigger EndMT.
• To explore signaling networks driving EndMT and counterbalancing mechanisms.
• To summarize methods for studying EC plasticity and discuss therapeutic strategies.

Main Methods:

• Review of in situ co-staining, genetic lineage tracing, epigenetic fate mapping, and single-cell multi-omics.
• Analysis of in vitro, organ-on-a-chip, and murine models of EC plasticity.
• Synthesis of evidence on atherogenic cues and signaling pathways.

Main Results:

• Atherogenic cues (disturbed flow, oxidative stress, inflammation, matrix stiffening) initiate EndMT.
• Convergent signaling networks (TGF-β, Wnt/β-catenin, Notch, NF-κB/STAT3, HDAC9) drive EndMT.
• Protective pathways (FGF, KLF2/KLF4) maintain endothelial homeostasis.
• Distinct disease-associated EC subpopulations identified through multi-omics.

Conclusions:

• EndMT is a critical cellular mechanism in atherosclerosis development.
• Understanding EC plasticity is key to developing targeted therapies.
• Precision medicine strategies can reprogram pathogenic endothelial states for plaque stabilization and vascular health.