Abstract 450: Vascular Smooth Muscle Cell-expressed Tie2 Controls Atherosclerosis Progression
Bibliographic record
Abstract
Angiopoietin (Angpt)/Tie signaling in microvascular endothelial cells (EC) controls vascular development, remodeling and maturation. Biomarker studies also imply a role of macrovascular Angpt/Tie signaling. The model of Angpt1/stimulation versus Angpt2/destabilization would imply an anti-atherosclerotic function of Angpt1 and a pro-atherosclerotic function of Angpt2. Yet, experimental studies on the role of the Angpt ligands and the Tie receptors in atherosclerosis have yielded conflicting results suggesting spatiotemporally context-dependent pro- and anti-atherosclerotic functions in different experimental settings. The endotheliocentric view of Angpt/Tie signaling is not sufficient to mechanistically explain the divergent roles of Angpt/Tie signaling during atherosclerosis. We hypothesized that vascular smooth muscle cell (VSMC)-expressed Tie2 may contribute to the pathogenesis of atherosclerosis. Employing genetic models, the present study was aimed at elucidating the role of VSMC-expressed Tie2 during atherosclerosis. Compared to EC, VSMC express lower, but consistently detectable levels of functional Tie2. We therefore generated VSMC-specific Tie2 - deficient mice ( Tie2 SMC-KO ), using a mural cell-specific Sm22α-Cre driver line. These were crossed with atherosclerosis-prone ApoE- deficient mice ( ApoE KO Tie2 SMC-KO ). ApoE KO Tie2 SMC-KO mice, fed a Western-type diet for 14 weeks, showed significantly reduced atherosclerotic lesion progression with less VSMC content. Transcriptionally, Tie2 controlled the phenotypic switch of VSMC with increased contractile and reduced synthetic phenotype-specific gene expression in isolated Tie2-deficient VSMC. Correspondingly, migration and proliferation was significantly reduced in Tie2-deficient cultured VSMC. Serum Angpt2 as well as the Angpt2/Angpt1 ratio were significantly increased in ApoE KO Tie2 SMC-KO mice. Collectively, the data expand and revise the endotheliocentric Tie2 signaling concept to show that mural cell-expressed Tie2 is involved in regulating macrovascular functions related to atherosclerosis. VSMC-expressed Tie2 acts pro-atherosclerotic to control the phenotypic switch towards a proliferative and migratory synthetic VSMC phenotype.
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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) | 0.005 | 0.001 |
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".