Paradigm Shift in Atherosclerosis: Endothelial Cells Form Coralthelial Foam Cells via Mechanical Stacking
For decades, textbook models attributed the origin of lipid-laden foam cells—the hallmark of early atherosclerotic fatty streaks—exclusively to two cell types: monocyte-derived macrophages and migrated vascular smooth muscle cells (VSMCs). Collaborative research by Prof. Fu (City College of New York) and Prof. Zeng (Sichuan University) now challenges this dogma with compelling evidence: physically stacked human aortic endothelial cells (HAECs) can independently transform into a novel foam-like subtype termed “coralthelial cells”, initiating fatty streak formation without the classic requirement for oxidized LDL (ox-LDL) induction.
1. Unique Morphological and Phenotypic Traits of Coralthelial Cells
In vitro 3D stacking culture without atherogenic additives or high-lipid media successfully drives HAEC phenotypic switching, characterized by:
2. Novel Organelle Mechanism: Golgi Nuclear Translocation and RPL23 Nucleolar Activation
The study reveals an unprecedented subcellular cascade linking mechanical stress to proinflammatory transformation:
This ER–Golgi–nucleolus mechanochemical axis represents the central molecular switch converting mechanical stacking signals into endothelial-to-foam cell conversion.
3. Robust Proinflammatory Secretome Drives Atherogenic Progression
RNA-seq analysis identified 339 differentially expressed genes between coralthelial cells and control HAECs, with strong enrichment in atherosclerosis-associated pathways (TNF, NF-κB, and cytokine-receptor interactions). Key findings include:
These secreted mediators promote leukocyte recruitment, thereby accelerating local atherosclerotic lesion development.
4. In Vivo Implications Resolve a Longstanding Clinical Puzzle
Atherosclerotic lesions preferentially develop at arterial bifurcations and curvatures, sites of disturbed blood flow that induce endothelial overturning and local cell stacking. This discovery elegantly explains the focal anatomical distribution of early fatty streaks. Furthermore, the finding that roughly 25% of foam cells in mature human plaques lack typical macrophage or VSMC markers can now be partly attributed to coralthelial (endothelium-derived) origins, addressing a major gap in current atherogenesis models.
Translational Prospects
1. Novel Therapeutic Targets: SAR1B, RPL23, and the Golgi nuclear translocation pathway emerge as promising candidates for anti-atherosclerotic drug development. Inhibiting this axis could block endothelium-derived foam cell formation and associated inflammation.
2. Mechanobiology-Driven Prevention: Strategies to optimize vascular hemodynamics and minimize pathological endothelial stacking (e.g., advanced stent designs that reduce disturbed shear stress) offer new preventive approaches.
3. Updated Disease Classification: The foam cell pool in atherosclerosis is now recognized as tripartite—macrophage-derived, VSMC-derived, and coralthelial/endothelium-derived—necessitating revised preclinical models and drug evaluation frameworks.
Closing Remark
This mechanobiology breakthrough fundamentally rewrites the early stages of atherosclerosis initiation. By demonstrating that pure mechanical stacking stress is sufficient to drive endothelial foam cell transformation—independent of lipid overload—the work establishes a powerful new research frontier focused on mechanical cues for cardiovascular disease prevention and precision therapeutics.
Mechanobiology in Medicine
News article
Stacked human aortic endothelial cells induce atherosclerotic fatty streaks and release proinflammatory cytokines and chemokines
1-Jun-2026