Pioglitazone inhibits HIF-1α-dependent angiogenesis in rats by paracrine and direct effects on endothelial cells
Bibliographic record
Abstract
UNLABELLED: Pioglitazone was associated with increased hazard for surgical or percutaneous lower extremity revascularization in patients with diabetes in a large clinical trial, but this clinical finding has not been adequately explored in animal models. We hypothesized that pioglitazone would decrease hypoxia-inducible factor 1α (HIF-1α)-dependent angiogenesis in rat ischemic hindlimb models by altering mitochondrial-derived signals supporting HIF-1α activation. We tested oral pioglitazone (10 mg/kg/day) versus placebo in two cohorts of rats with hindlimb ischemia (normal Sprague-Dawley rats and insulin-resistant JCR:La-cp rats), and evaluated direct and paracrine effects of pioglitazone on angiogenesis in vitro using human skeletal muscle and endothelial cells. Pioglitazone treatment was associated with reductions in limb perfusion at 2 weeks measured by contrast-enhanced ultrasound and Tc(99m)-Sestamibi SPECT-CT. Ischemic muscle capillary density was also reduced by pioglitazone. HIF-1α and vascular endothelial growth factor (VEGF) expression in ischemic muscle were also reduced by pioglitazone. In vitro, pioglitazone's effects on both skeletal muscle cells and microvascular endothelial cells were associated with a decrease in autocrine and paracrine angiogenesis measured by matrigel assay, decreased HIF-1α expression and activation, as well as increases in both mitochondrial reactive oxygen species and α-ketoglutarate, both mitochondria-derived signals which promote HIF-1α degradation. We conclude that pioglitazone is associated with decreased ischemic limb perfusion and capillary density in relevant rat models of hindlimb ischemia, and these effects are mediated by mitochondria-dependent reductions in HIF-1α-dependent angiogenesis. KEY MESSAGES: Pioglitazone inhibits angiogenesis in rats with and without insulin resistance. Pioglitazone inhibits HIF-1α by inhibiting mitochondrial stabilization of HIF-1. Pioglitazone inhibits both autocrine and paracrine angiogenesis. Inhibition of angiogenesis may explain unexpected results of a pioglitazone human clinical trial.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
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".