Abstract 242: Microvascular Stenosis in End-Stage Peripheral Artery Disease: Role of Partial Endothelial to Mesenchymal Transition
Bibliographic record
Abstract
Peripheral artery disease (PAD) is a widespread and debilitating manifestation of atherosclerosis. Unfortunately, revascularization strategies are often precluded or unsuccessful, resulting in amputation. A major reason for treatment failure is likely co-existing abnormalities in the distal microvasculature. However, the specific microvascular defects present in end-stage PAD in humans remain unknown. To elucidate the microvascular landscape in PAD, we studied human tibialis anterior (TA, n=18) and gastrocnemius (n=13) muscles harvested from below-knee leg amputations of 10 individuals with end-stage PAD. Control muscles, from individuals without PAD, were obtained from TA (n=2) and vastus lateralis (n=4) samples. PAD but not control samples had myofiber damage features. Interestingly, capillary density, quantified from CD31-stained sections, was 2.1-fold higher in PAD tissue (p=0.005). Furthermore, the PAD capillaries were atypical, with a 1.7-fold increase in smooth muscle-α-actin-containing mural cells (p<0.001). Surprisingly, the arterioles (15-40 μm) in subjects with PAD were found to be stenotic, with 28% decrease in lumen area (p=0.0018). Moreover, 11% of the stenotic arterioles in the lower tertile of size were entirely occluded. Microvascular stenosis was EC-based, with pronounced nuclear rounding (p=0.03) and luminal encroachment. These aberrant ECs were CD31-positive but also expressed mesenchymal markers N-cadherin, S100A4, and SLUG, indicating partial endothelial to mesenchymal transition (EndMT). As well, the mural cells of PAD arterioles expressed higher TGFß than control arterioles. Finally, using a novel microfluidic device with fully EC-lined micro-channels, we identified pronounced inward bulging and lumen encroachment of ECs when subjected to ultra-low flow and fluid shear stresses below 0.5 dynes/cm 2 (p<0.001). Conclusions: These studies reveal EC-based microvascular stenosis as a previously unidentified feature of end-stage PAD. Ultra-low shear stress, TGFß signalling, and partial EndMT are implicated in driving this novel micro-luminal obstruction process.
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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) | 0.003 | 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".