Forkhead BoxO transcription factors restrain exercise‐induced angiogenesis
Bibliographic record
Abstract
Key points The growth of new capillaries, angiogenesis, within skeletal muscle occurs only after weeks of repeated aerobic exercise. Paradoxically, large increases in pro‐angiogenic factors such as vascular endothelial growth factor occur with a single exercise bout. The mechanisms underlying the substantial lag in the angiogenic response remain to be elucidated. We detected concomitant increases in the angiostatic Forkhead Box ‘O’ transcription factors FoxO1 and FoxO3a and the matrix protein thrombospondin‐1 following a single bout of exercise, but these responses were repressed after 10 days of repeated exercise. This observation led us to hypothesize that FoxO proteins delay the initiation of exercise‐induced angiogenesis. Endothelial cell‐directed deletion of FoxO proteins abolished the increase in thrombospondin‐1 following a single exercise bout, and resulted in a substantially accelerated angiogenic response. This study identifies an intrinsic endothelial‐specific FoxO signalling pathway that opposes the onset of physiological angiogenesis within healthy exercising skeletal muscle and demonstrates that endothelial cell FoxO proteins are critical determinants of the angiogenic capacity within skeletal muscle. Abstract The physiological process of exercise‐induced angiogenesis involves the orchestrated upregulation of angiogenic factors together with repression of angiostatic factors. The Forkhead Box ‘O’ (FoxO) transcription factors promote an angiostatic environment in pathological contexts. We hypothesized that endothelial FoxO1 and FoxO3a also play an integral role in restricting the angiogenic response to aerobic exercise training. A single exercise bout significantly increased levels of FoxO1 and FoxO3a mRNA (5.5‐ and 1.7‐fold, respectively) and protein (1.7‐ and 2.2‐fold, respectively) within the muscles of mice 2 h post‐exercise compared to sedentary. Training abolished the exercise‐induced increases in both FoxO1 and FoxO3a mRNA and proteins, and resulted in significantly lower nuclear levels of FoxO1 and FoxO3a protein (0.5‐ and 0.4‐fold, respectively, relative to sedentary). Thrombospondin 1 (THBS1) protein level closely mirrored the expression pattern of FoxO proteins. The 1.7‐fold increase in THBS1 protein following acute exercise no longer occurred after 10 days of repeated exercise. Endothelial cell‐directed conditional deletion of FoxO1/3a/4 in mice prevented the increase in THBS1 mRNA following a single exercise bout. Mice harbouring the endothelial FoxO deletion also demonstrated a significant 20% increase in capillary to muscle fibre ratio after only 7 days of training while 14 days of training was required to elicit a similar increase in wildtype littermates. Our results demonstrate that the downregulation of FoxO1 and FoxO3a proteins facilitates angiogenesis in response to repeated exercise. In conclusion, FoxO proteins can delay exercise‐induced angiogenesis, and thus are critical regulators of the physiological angiogenic response in skeletal muscle.
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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".