The Role of Scleraxis in Inducing Vascular Stiffness
Bibliographic record
Abstract
Vascular fibrosis (VF) is one of the most significant pathologies related to blood vessel dysfunction. VF results in an impairment of vascular tone due to an increase in extracellular matrix proteins (ECM) and vascular smooth muscle synthesis within the vessel wall, thus increasing vascular stiffness and reducing lumen diameter. VF is both caused by and exacerbates numerous vascular diseases including diabetes, atherosclerosis and in particular, hypertension, which accounts for 13% of deaths globally (WHO World Health Report, 2002). Multiple studies have investigated various therapeutic approaches to interfere with VF, but to date this condition remains untreated, thus novel approaches to target fibrosis development and progression are urgently required. Our lab identified the transcription factor scleraxis as a novel master regulator of cellular phenotype conversion. We demonstrated that scleraxis is sufficient to induce fibroblast to myofibroblast phenotype conversion, a critical step in the development of fibrosis in many tissue types. Scleraxis also induces Epithelial to Mesenchymal Transition (EMT) and cell migration as part of development and cell differentiation. Some studies have shown that mechanical stretch in tendons increases expression of scleraxis, while additional studies reported that stretch in rabbit aorta induces the vascular smooth muscle proliferative phenotype. Our preliminary data has revealed that scleraxis is expressed in VSMCs in the arterial wall, and we have found elevated scleraxis expression in high pressure versus low pressure regions of vessels. We thus hypothesize that scleraxis is sufficient and necessary to induce vascular fibrosis. Our data shows that scleraxis overexpression increases thickness of the aortic vascular wall in scleraxis overexpression mice, via histological sections, thus contributing to the progression of vascular fibrosis. In vitro studies show that scleraxis overexpression in Human Aortic Smooth Muscle Cells (HAOSMC) induces their proliferation and migration using different assays (CCk8/Edu+ proliferation assay, Transwell migration assay, gene expression assays). Scleraxis overexpression also induces hypertrophy of HAOSMC shown via immunostaining. This suggests that scleraxis overexpression induces VSMC plasticity from contractile to synthetic‐proliferative phenotype, thus inducing VSMC hyperplasia. New & Noteworthy: Our findings indicate that scleraxis plays a role in VSMC plasticity via scleraxis‐ mediated transcriptional regulation of VSMC proliferation and migration. This work has potential relevance to many related diseases that feature VSMC activation, including atherosclerosis and restenosis.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 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 teacher head, 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".