Endothelial Stiffening Induced by CD36-Mediated Lipid Uptake Leads to Endothelial Barrier Disruption and Contributes to Atherosclerotic Lesions
Bibliographic record
Abstract
BACKGROUND: Endothelial stiffening induced by Western diet was proposed to be an important factor in vascular dysfunction. In this study, we determine the role of endothelial CD36 (cluster of differentiation 36) in stiffening, disruption of aortic endothelial barrier, and atherosclerosis in mouse models of obesity and hypercholesterolemia. METHODS: To address this goal, we generated an endothelial-specific inducible knockdown mouse model of CD36, Cdh5.CreER T2 CD36 fl/fl , on C57/BL6J wild-type and LDLR −/− genetic backgrounds. Endothelial stiffness is assessed by atomic force microscopy; endothelial barrier integrity is assessed by imaging VE (vascular endothelium)-cadherin junctions and by penetration of Evans blue dye into the aortic wall. Atherosclerotic plaques are quantified using oil red O staining. RESULTS: Endothelial-specific downregulation of CD36 abrogates stiffening of aortic endothelium induced by Western diet in Cdh5.CreER T2 CD36 fl/fl and in Cdh5.CreER T2 CD36 fl/fl LDLR −/− mice. Prevention of Western diet–induced endothelial stiffening by downregulation of CD36 is associated with a protective effect against endothelial barrier disruption in both mouse models and with a significant decrease in the areas of atherosclerotic lesions in Cdh5.CreER T2 CD36 fl/fl LDLR −/− mice. Mechanistically, stiffening of human aortic endothelial cells in vitro is induced by saturated fatty acids, particularly palmitic acid (PA), which results in activation of RhoA. Both PA-induced endothelial stiffening and RhoA activation are abrogated by CD36 siRNA. Furthermore, PA-induced endothelial stiffening of excised aortas ex vivo is lost in aortas isolated from mice, where endothelial CD36 is downregulated. We also demonstrate that PA-induced activation of RhoA and endothelial stiffening require expressing an RhoA-inhibitory protein, Rho-GDI1 (Rho guanosine dissociation inhibitor 1). Finally, we discover that PA disrupts the colocalization of RhoA with Rho-GDI1. CONCLUSIONS: We conclude that stiffening of the aortic endothelium by CD36-mediated uptake of fatty acids contributes significantly to Western diet–induced vascular dysfunction and atherosclerosis. We further propose that fatty acids may activate RhoA by inducing its dissociation from Rho-GDI1.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".