87. Angiotensin II Type 2 Receptor Signal Modulation in Models of Cutaneous Wound Healing
Bibliographic record
Abstract
PURPOSE: Globally, hypertrophic scarring remains a major burden for patients, resulting in significant aesthetic and functional morbidity. A variety of methods that target cellular pathways during wound healing have been proposed to reduce skin scarring. One candidate target is the angiotensin II type 2 receptor (AT2R), whose signaling has been shown to be antifibrotic. Compound 21 (C21) is a selective AT2R agonist previously shown in vitro and in vivo to reduce cardiac and renal fibrosis by limiting myofibroblast activity and collagen production. We sought to modulate AT2R signaling using C21 and the AT2R antagonist, PD123319, in models of cutaneous wound healing to determine whether this pathway can be exploited to reduce scarring. METHODS: A splinted wound model was employed in mice to recapitulate early phases of the tethered-skin wound healing observed in humans. Ten-week-old male Balb/c mice received two, full-thickness dorsal skin wounds that were splinted with silicone rings and covered with a semipermeable membrane. On alternating days, one wound received topical 20uM C21 (n=12) or PD123319 (10uM; n=8), while the other received saline vehicle, until sacrifice on day 10. Wounds, including surrounding healthy skin, were then harvested for histology and qPCR analyses. Scratch assays were performed on human dermal fibroblasts and keratinocytes to assess C21 and PD123319 activity in vitro. RESULTS: C21 treatment did not affect the rate of reepithelialisation, while PD123319 treatment accelerated wound closure (p=0.03 vs saline). Collagen density was increased in C21-treated wounds (p=0.01 vs saline), similar to normal unwounded skin, but was decreased with PD123319 treatment (p=0.04 vs saline and 0.0001 vs C21). C21 also increased vascular density relative to saline (p=0.01). We observed upregulation of genes associated with regeneration and repair including Col6a1 (p=0.007), NGF (p=0.012), and mast cell markers Ms4a2 (p=0.001) and Tpsb2 (p=0.009) with C21 treatment, while PD123319 treatment reduced Col1a1 gene expression (p=0.047). C21-treated wounds had a marked reduction in immune cell infiltration compared to PD123319 and saline-treated wounds and more closely resembled normal skin. Similarly, 50uM C21 reduced both fibroblast (p<0.0001 vs vehicle) and keratinocyte (p=0.004 vs PD123319) migration via scratch assay in vitro. CONCLUSION: In our early wound healing model, AT2R activation was associated with collagen density comparable to that of unwounded skin and increased vascular density. Inhibition of AT2R led to rapid re-epithelialization and reduced collagen deposition consistent with atrophic wounds. We are also addressing the possibility of a mast cell-related mechanism with future experiments. AT2R signal modulation is, therefore, a potential therapeutic target to improve skin quality during wound healing.
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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) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.001 |
| 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".