Abstract 190: Deletion Of Shp-1 Prevents Diabetes-induced Endothelial Cell Senescence And Restores Blood Flow Reperfusion Following Ischemia
Bibliographic record
Abstract
Introduction: Ischemia due to narrowing of the femoral artery and distal vessels is also a major cause of peripheral arterial disease and morbidity affecting patients with diabetes. Diabetes-induced premature senescence of endothelial cells has been shown as a potential mechanism of poor angiogenic response to ischemia. Our laboratory has previously shown that hyperglycemia reduced vascular endothelial growth factor (VEGF) activity in ischemic muscle of diabetic mice, which was associated with increased SHP-1 expression, a protein tyrosine phosphatase. The objective of this study is to evaluate the impact of SHP-1 deletion on endothelial cell function and senescence both in vitro and in vivo . Methods: Non-diabetic (NDM) and 3 months diabetic (DM) mice with deletion of SHP-1 specifically in endothelial cells (EC) were used. Ligation of the femoral artery was performed, and blood flow reperfusion was measured by laser Doppler for 4 weeks. Primary EC were exposed to normal (5.6 mM; NG) or high glucose concentrations (25 mM; HG) for 48 h, in normoxia (20% oxygen) or hypoxia (1%) for the last 16h in presence of VEGF. Results: Blood flow reperfusion and limb function (voluntary running wheel) were reduced by 50% and 91%, respectively in DM mice as compared to NDM mice. Specific EC deletion of SHP-1 restored blood flow reperfusion by 55%, limb function by 37% and capillary density in DM mice. Moreover, ablation of SHP-1 only in EC prevented diabetes-induced p21 expression and reduction of Nrf-2. In cultured EC , overexpression of dominant negative of SHP-1 prevented HG-induced inhibition of proliferation, migration, and VEGFR2/Akt phosphorylation following VEGF stimulation. In addition, the expression of senescence markers (increased p21 and beta-galactosidase; reduced Nrf-2) in EC exposed to HG levels were reversed by overexpression of SHP-1 dominant negative. Conclusion: Ablation of SHP-1 expression in EC resulted in the prevention of hyperglycemia-induced EC senescence, reduction of VEGF actions, poor collateral vessel formation and blood flow reperfusion.
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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) | 0.000 | 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 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 0.001 |
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".