Abstract 16511: Discoidin Domain Receptor-1: A Novel Molecular Switch Regulating Fibrocalcific Response in Vascular Smooth Muscle Cells
Bibliographic record
Abstract
Background: Extracellular vesicle (EV)-derived microcalcifications formed in collagen-poor fibrous caps contribute to plaque rupture. Collagen accumulation and calcification are major determinants of plaque stability, although the mechanisms linking fibrotic and calcific responses are unknown. The collagen receptor discoidin domain receptor-1 (DDR-1) regulates plaque calcification in vivo ; however, its role in the release of calcifying EVs remains unclear. We hypothesize that DDR-1 regulates the processes of fibrosis and EV-induced calcification in atherosclerotic plaques. Methods and results: Smooth muscle cells (SMC) from the carotid arteries of wild type and DDR-1 knockout (DDR-1 -/- ) mice (n=5 per group) were cultured in control or calcifying media. At days 14 and 21, cells were harvested and EVs isolated for analysis. Compared to wild type cells, DDR-1 -/- SMCs exhibited a 3.5-fold increase in EV release (p<0.001) as well as elevated EV calcifying potential determined by EV-bound alkaline phosphatase (ALP) activity (470.4±30.0 vs. 19.1±2.3 ng/well/mg protein). DDR-1 -/- SMCs showed an increase in ALP activity (220.3±31.2 vs. 6.9±1.2 ng/well/mg protein), calcification measured by alizarin red S absorbance (3.56±0.11 vs. 0.10±0.0008), and collagen type I accumulation (p=0.04). Transforming growth factor-β (TGFβ) signaling has been implicated in both fibrotic and calcific responses. DDR-1 -/- cells released significantly more TGFβ in calcifying medium (253.4±12.4 vs. 167.2±8.8 pg/ml, p<0.001), suggesting a connection between DDR-1 and TGFβ signaling. A selective TGFβ receptor I inhibitor mitigated the osteogenic potential of the DDR-1 -/- phenotype with a significant decrease in EV release, ALP activity in SMCs and EVs, extracellular matrix calcification and collagen production. Analysis of TGFβ-associated pathways in DDR-1 -/- SMCs revealed significantly increased p38 phosphorylation while phosphorylated Smad3 and JNK were inhibited. Conclusion: DDR-1 interferes with TGFβ-mediated p38 phosphorylation to restrict EV-induced calcification. DDR-1 concomitantly attenuates collagen accumulation in vascular SMCs, establishing a novel mechanism of cell-matrix interaction in arterial fibrocalcific responses.
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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 | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.003 | 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".