Endothelial Foxo1 and Foxo3a Synergistically Repress Skeletal Muscle Vascular Growth and Blood Flow Recovery in a Mouse Model of Hind Limb Ischemia.
Bibliographic record
Abstract
Neovascularization in peripheral artery disease (PAD) is impaired despite upregulation of factors that promote blood vessel growth which suggest a concomitant increase of anti‐angiogenic repressors. We previously showed that depletion of FoxO proteins (FoxO1/3a/4) induced angiogenesis and enhanced blood flow recovery in a mouse model of PAD. The purpose of this study is to independently assess the roles of endothelial FoxO1 and synergistic actions of FoxO 1 & 3a in a mouse model of PAD. Mice with tamoxifen‐inducible endothelial specific deletions of FoxO1 (PDGFBCreER T2 +;FoxO1 L/L , FoxO1 Δ ) and FoxO1/3a (PDGFBCreER T2 +;FoxO1/3a L/L , FoxO1/3 Δ ), or control (PDGFBCreER T2 ‐, FoxO1 L/L ) mice, underwent unilateral ligation of the common femoral artery (at ~8–9 weeks of age) to induce a substantial (~80%) reduction of blood flow in the ligated (LIG) compared to the contralateral (CON) leg. Blood flow recovery was analyzed by laser doppler imaging at baseline, then on days 4, 7, 10 and 14 post‐ligation. Muscle histology was conducted after 14 days. FoxO1/3 Δ blood flow (LIG/CON leg perfusion ratio) was recovered to basal levels (1.10 ±0.07; n=6) and significantly greater than FoxO1 Δ (0.73 ±0.05; P <0.01, n=5) and FoxO1 L/L (0.65 ±0.03; P <0.001, n=5) mice 14 days post‐ligation. Neither FoxO1 nor FoxO1/3 deletion altered capillary density (CD) in the control leg. In contrast, CON leg capillary‐to‐fibre ratio (C: F) in FoxO1/3 Δ mice (1.02 ±0.04) was significantly lower than FoxO1 L/L (1.48 ±0.08) and FoxO1 Δ (1.44 ±0.09) mice ( P <0.05). Ischemic muscle was characterized by marked cellular infiltration, deposition of fibrous and adipose tissue and myofibre atrophy. Capillary density was significantly increased in ischemic muscles from FoxO1 Δ (CON: 746 ±40.15 vs LIG: 1218 ±187.4 capillaries/mm 2 ; P =0.03) and FoxO1/3a Δ (CON: 743.2 ±39.35 vs LIG: 1661 ±158.5 capillaries/mm 2 ; P =0.005) mice. C: F was increased ~25% in ischemic muscle from FoxO1/3 Δ mice (1.28 ±0.05; P <0.05 ) but was unaltered in FoxO1 L/L (1.46 ±0.19) or FoxO1 Δ mice (1.55 ±0.22). Our data suggest that the combined effects of FoxO1 & 3a repress vascular growth and blood flow recovery in ischemic muscles more than the independent effects of FoxO1. Funded by CIHR.
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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 | 0.000 | 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 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".