Mechanobiology breakthrough reshapes understanding of atherosclerosis: Stacked endothelial cells transform into novel foam cells, unlocking new targets for anti-lipid and anti-inflammatory therapies

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:

• Distinct coral-like, bleb-studded surface ultrastructure visible under scanning electron microscopy (SEM), markedly different from the typical cobblestone morphology of endothelial monolayers;
• Cytoskeletal collapse, with F-actin fluorescence intensity reduced to ~11.8% of normal monolayer HAECs and nuclear size shrinking to less than half the original volume;
• Massive intracellular lipid accumulation (~10-fold increase in lipid droplets compared to regular endothelial cells), confirmed by Oil Red O and BODIPY dual staining;
• Partial loss of endothelial identity, with canonical markers CD31 and FVIII dropping to ~20% and ~31% of baseline levels, respectively, while acquiring foam cell-like lipid-handling properties.

2. Novel Organelle Mechanism: Golgi Nuclear Translocation and RPL23 Nucleolar Activation

The study reveals an unprecedented subcellular cascade linking mechanical stress to proinflammatory transformation:

• Cytoplasm-restricted Golgi apparatus (marked by GM130) and the COPII vesicle component SAR1B translocate into the nuclei of coralthelial cells;
• Ribosomal protein RPL23 abnormally accumulates in the nucleolus, accompanied by nucleolar stress;
• siRNA-mediated silencing of SAR1B or RPL23 blocks Golgi nuclear trafficking, prevents RPL23 nucleolar enrichment, and strongly suppresses proinflammatory mediator release.

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:

• qPCR validation of sharp upregulation of IL-6 (~7.2-fold), MCP-1 (~12.7-fold), and CXCL8 (~5.3-fold) in stacked coralthelial cells;
• Time-course ELISA demonstrating progressive increases in these chemokines over 2–11 days of culture, with day-11 levels dramatically exceeding monolayer controls (e.g., CXCL8: 7385.8 vs. 1079.0 pg/mL).

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.