The Role of the Discoidin Domain Receptor-1 (DDR1) in Vascular Smooth Muscle Cell (VSMC) Mechanosensing
Bibliographic record
Abstract
Mechanotransduction is the process by which extracellular physical cues are converted into intracellular biochemical responses. The stiffness of the matrix influences numerous processes such as cell differentiation, cell migration, fibrosis, and tumorigenesis. Stiffness is sensed by matrix-binding receptors and transmitted through the cytoskeleton by actomyosin contractility. The work presented in this thesis identifies how Discoidin Domain Receptor-1 (DDR1) mediates stiffness sensing and how this influences vascular smooth muscle cell (VSMC) calcification. In the first study, experiments in primary murine Ddr1+/+ or Ddr1-/- VSMCs revealed that DDR1 promotes VSMC calcification in a stiffness-dependent manner by a positive feedback loop between DDR1 and actomyosin contractility. Increased matrix stiffness promoted increased nuclear RUNX2 levels, increased DDR1 activation and expression, increased Vav2-RhoA activity, and increased stress fibre formation in Ddr1+/+ but not Ddr1-/- VSMCs. RhoA activation increased DDR1 expression and activity independent of ligand, whereas inhibition of RhoA and actomyosin contractility were inhibitory. RUNX2 activity and expression, and VSMC calcification were increased by actomyosin contractility. The second study shows that regulation of stiffness-sensitive genes is mediated by a DDR1-YAP/TAZ nuclear complex. Ddr1-/- VSMCs had reduced nuclear YAP/TAZ, and loss of YAP/TAZ resulted in decreased DDR1 expression. DDR1 activation and increased substrate stiffness promoted DDR1 and YAP/TAZ nuclear localization. DDR1 and YAP/TAZ nuclear translocation were dependent on actomyosin contractility and caveolae. Increased stiffness, collagen stimulation, and RhoA activation all promoted DDR1 and YAP/TAZ localization to the chromatin. Collagen stimulation and RhoA activation stimulated the formation of a DDR1-YAP/TAZ-RNA polymerase II nuclear complex. Finally, DDR1 was found to localize to the promoters of Ddr1 and the canonical YAP/TAZ target gene Ctgf. In summary, these studies show a key role for DDR1 as a stiffness sensor in vascular smooth muscle cells to influence vascular pathologies like vascular calcification. DDR1 can mediate mechanosignaling via a positive feedback loop between DDR1 and actomyosin contractility, and through direct regulation of mechanosensitive genes like Ddr1 itself by a nuclear DDR1-YAP/TAZ complex. This research highlights the role of matrix stiffness in promoting vascular calcification, but also uncovers novel downstream pathways by which DDR1 mechanosignaling occurs at the membrane and in the nucleus.
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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 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 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".