Endothelial-to-mesenchymal transition drives atherosclerosis progression

Area of Science:

• Cardiovascular Biology
• Cellular Biology
• Molecular Medicine

Background:

• Atherosclerosis pathogenesis remains incompletely understood.
• Endothelial-to-mesenchymal transition (EndMT) is implicated in cardiovascular disease.
• The role of FGF receptor 1 (FGFR1) in EndMT and atherosclerosis requires elucidation.

Purpose of the Study:

• To investigate the role of endothelial FGFR1 and EndMT in atherosclerosis.
• To determine the impact of disrupted FGF signaling on atherosclerotic lesion development.
• To assess the clinical relevance of endothelial FGFR1, EndMT, and TGF-β signaling in human coronary artery disease.

Main Methods:

• In vitro studies using cultured human endothelial cells exposed to inflammatory cytokines and shear stress.
• In vivo studies using endothelial-specific Frs2a deletion in Apoe(-/-) mice on a high-fat diet.
• Molecular and morphometric analysis of human coronary artery samples from patients with varying degrees of coronary disease.

Main Results:

• Reduced endothelial FGFR1 expression and activated TGF-β signaling were observed under inflammatory and shear stress conditions.
• Endothelial-specific Frs2a deletion in Apoe(-/-) mice accelerated atherosclerosis development, increasing plaque burden by 84%.
• Accelerated atherosclerosis was associated with increased EndMT, fibronectin deposition, and neointima formation.
• Human coronary atherosclerosis severity correlated with decreased endothelial FGFR1 expression, activated TGF-β signaling, and extent of EndMT.

Conclusions:

• Loss of protective endothelial FGFR signaling promotes atherosclerosis progression.
• Endothelial-to-mesenchymal transition (EndMT) is a key mediator linking FGFR signaling loss to atherosclerosis.
• These findings highlight a novel molecular pathway contributing to cardiovascular disease and suggest potential therapeutic targets.