Abstract 104: Early Rescue of Lymphatic Function Limits Atherosclerosis Progression in <i> Ldlr <sup>-/-</sup> </i> Mice
Bibliographic record
Abstract
Background: Lymphatic function impairment occurs before the onset of atherosclerosis in mice and is precociously associated with a defect in the propelling capacity of the collecting lymphatic vessels (LV). Lymphatic transport can be restored in mice by systemic injections of a mutant form of VEGF-C (VEGF-C 152s). In the present study, we aimed to determine whether and how early modulation of collecting LV function could restrain atherosclerosis onset and limit its progression. Methods: Ldlr -/- mice at 6 weeks of age were injected intraperitoneally with VEGF-C 152s or with PBS every other day for 4 weeks, fed on high fat diet (HFD) for an additional 8 weeks to promote plaque progression, and switched back on chow diet for 4 more weeks to stabilize the lesion. Results: Early treatment with VEGF-C 152s first improved lymphatic molecular transport in 6-week-old Ldlr -/- mice and subsequently limited plaque and macrophage accumulation, while improving inflammatory cell migration through the lymphatics in HFD-fed mice. The contraction frequency of the collecting LVs was significantly increased following treatment throughout the whole atherosclerotic process and resulted in enhanced plaque stabilization. This early and maintained rescue of the lymphatic dysfunction was associated with an upregulation of VEGFR3 and FOXC2 expression on lymphatic endothelial cells, albeit without modifying eNOS expression. Systemic injections with VEGF-C 152s did not initially alter mice cholesterol levels and lipoprotein profile. Unsurprisingly, total plasma cholesterol levels increased when the pro-atherogenic regimen was applied and an improved absorptive capacity of the mesenteric LVs was reflected by the presence of chylomicron remnants and lower levels of VLDL and LDL/IDL in the VEGF-C-treated group. VEGF-C 152s also did not significantly modulate HDL levels throughout the process. This indicates that VEGF-C-dependant stimulation of lymphatic function, independent of cholesterol levels, is responsible for subsequent atherosclerotic plaque buildup. Conclusions: Early treatments that specifically target the lymphatic contraction capacity prior to lesion formation might be a novel therapeutic approach for the prevention and treatment of atherosclerosis.
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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) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.002 |
| Insufficient payload (model declined to judge) | 0.006 | 0.002 |
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".