Abstract Tu0048: The ETS Transcription Factor ERG Drives Endothelial Cell Resilience And Guards Against Atherosclerosis
Bibliographic record
Abstract
Aim: The ETS transcription factor ERG supports endothelial function by repressing inflammation and maintaining endothelial cell (EC) identity in healthy vasculature. Loss of ERG induces endothelial to mesenchymal transition (EndMT) and exacerbates chronic inflammatory diseases. To investigate ERG function in atherosclerosis, we leveraged an EC-specific Erg knockout ( Erg EC-KO ) in a PCSK9-overexpression murine atherosclerosis model. Methods: Atherosclerosis was induced in 10-week-old Erg EC-KO or control mice that had a Cre-inducible EC lineage tag ( Cdh5 CreERT2 ; R26-CAG-LSL-Sun1-sfGFP ) with AAV8-PCSK9 and 12 weeks of high-cholesterol diet (HCD, 1.25%). Plaque burden and morphology were characterized with Oil Red O, H&E, Movat, and immunofluorescence imaging. Aortic intimal cells were isolated with gentle digestion and profiled with single-cell RNA sequencing (scRNA-seq) in early and late plaque (4 and 12 weeks of HCD, n=6 mice/sample). Endothelial permeability was assessed with accumulation of IV TRITC-dextran (70 kDa) or DiI-LDL. Results: Loss of ERG led to a 1.6-fold increase in aortic plaque burden and plaque formation at atheroprotective sites (greater curvature; p≤0.03; n=9-10). A 5.3-fold increase in EC lineage cells was observed in brachiocephalic artery plaques (p=0.0001; n=6-15), which underwent EndMT (31.5-fold increase in GFP + ACTA2 + cells, p=0.02, n=3-5). Aortic intimal scRNA-seq in early plaque revealed increased proportions of inflammatory macrophages and foam cells in Erg EC-KO mice (6.9 and 2.7-fold). Erg EC-KO ECs showed a marked loss of endothelial identity (67 transcripts including Nos3 , Tek , Vwf , p=1.42e -91 ) that preceded the gain of mesenchymal traits in late plaque (66 transcripts including Col8a1 , Fbln5 , Vim , p=1.19e -96 ). Pathway and ligand-receptor analyses highlighted alterations in cell adhesion ( Cadm1 , Gja5 ) and migration programs ( Sdc4 ), which were confirmed with increased endothelial permeability prior to atherosclerosis (TRITC-dextran, p=0.0007, n=8) and increased monocyte LDL uptake in early plaque (p=0.04, n=7-9). Conclusion: Endothelial Erg KO increases plaque burden in murine atherosclerosis. Loss of ERG promotes EndMT and marked ingression of ECs from the luminal endothelium to the plaque interior, which is associated with increased permeability and lipid accumulation. These findings implicate ERG dysfunction as a novel mechanism by which EC identity and resilience are compromised in atherosclerotic cardiovascular disease.
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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 | 0.001 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.001 | 0.002 |
| Insufficient payload (model declined to judge) | 0.013 | 0.003 |
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".