Abstract 461: Sildenafil Improves Ischemia-Induced Neovascularization in ApoE-Deficient Mice
Bibliographic record
Abstract
Background: Sildenafil is widely used to treat erectile dysfunction. Sildenafil inhibits phospho-diesterase 5 (PDE5), thereby increasing cGMP levels in target tissues. The NO-cGMP pathway has been shown to be essential for angiogenesis, vasculogenesis and postnatal neovascularization. Therefore, here we tested the hypothesis that sildenafil might improve neovascularization following ischemia. Methods and results: Hypercholesterolemic ApoE−/− mice, which are characterised by reduced neovascularization in response to ischemia, were treated or not with sildenafil (40 mg/kg/day in water) for the whole duration of the study. Sildenafil was well tolerated by ApoE−/− mice and led to a significant increase of plasmatic cGMP levels compared to controls (13.4±1.9 vs. 4.6±2.6 pmol/mL, p<0.05). After two weeks of treatment, hindlimb ischemia was surgically induced by femoral artery removal. Sildenafil treatment led to a significantly faster rate of blood flow recovery, as assessed by Laser Doppler measurement at day 7 after surgery (55.5% increase, p<0.05). We found that sildenafil treatment is associated with an increased activation of angiogenic transduction pathways such as Akt, p44/42 MAPK, and p38 in ischemic muscles (phosphospecific Western blots). Moreover, sildenafil treatment leads to a significant reduction of oxidative stress in ischemic tissues (nitrotyrosine staining). Endothelial progenitor cells (EPCs) have been shown to participate to postnatal neovascularization. We found that ApoE−/− mice treated with sildenafil have a significant increase in the number of bone marrow EPCs (DiI-AcLDL and FITC-Lectin staining) compared to untreated mice (272±18 vs. 187±17 cells per field, p<0.05). Moreover, the adhesion (19.7±2.1 vs. 10.0±1.9 EPCs per field, p<0.05) and the migratory capacity (28.5±1.8 vs. 15.2±1.3 EPCs per field, p<0.0001) of EPCs are significantly improved in ApoE−/− mice treated with sildenafil. Conclusions: Sildenafil treatment is associated with improved ischemia-induced neovascularization in hypercholesterolemic conditions. The mechanisms involve beneficial effects of sildenafil on angiogenic pathways in ischemic tissues together with an increase in the number and the functional activity of EPCs.
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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) | 0.002 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.005 | 0.002 |
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".