Endothelial SHP-1 regulates diabetes-induced abnormal collateral vessel formation and endothelial cell senescence
Bibliographic record
Abstract
Abstract Objective Ischemia due to narrowing of the femoral artery and distal vessels is a major cause of peripheral arterial disease and morbidity affecting patients with diabetes. Diabetes-induced premature senescence of endothelial cells (EC) has been proposed as a mechanism leading to impaired ischemia-driven angiogenesis. Importantly, our previous work has shown that hyperglycemia reduced vascular endothelial growth factor (VEGF) activity in ischemic muscle of diabetic mice, which was associated with increased expression of the protein tyrosine phosphatase Src homology region 2 domain-containing phosphatase-1 (SHP-1). Here, we evaluate the impact of SHP-1 deletion on EC function and senescence. Approach and Results Ligation of the femoral artery was performed in nondiabetic (NDM) and 3 months diabetic (DM) mice with EC-specific deletion of SHP-1 and blood flow reperfusion was measured for 4 weeks. Blood flow reperfusion and limb function during voluntary wheel running were reduced by 43% and 82%, respectively in DM mice as compared to NDM mice. EC-specific deletion of SHP-1 in DM mice restored blood flow reperfusion by 60%, limb function by 86%, while capillary density was similar to NDM mice. Moreover, ablation of SHP-1 in EC prevented diabetes-induced expression of the senescence markers p53 and p21 and counteracted Nrf2 downregulation. In cultured EC, overexpression of dominant negative of SHP-1 prevented HG-induced inhibition of proliferation, migration, tubule formation and VEGFR2/Akt phosphorylation following VEGF stimulation. In addition, the expression of senescence markers and suppression of Nrf2 in EC exposed to HG levels were reversed by overexpression of dominant negative SHP-1. Conclusion SHP-1 in ECs is a central effector of diabetes-induced senescence that blocks VEGF action, and induces aberrant collateral vessel formation and blood flow reperfusion. Reduced SHP-1 expression counteracts these pathologic features suggesting the notion that it represents a promising therapeutic target. HIGHLIGHTS Endothelial specific deletion of SHP-1 (Scr homology 2-containing phosphatase-1) improves blood flow reperfusion, limb motricity and vessel density in the diabetic ischemic limb. Diabetes-induced SHP-1 protein expression inhibits VEGF proangiogenic actions and promotes endothelial senescence. Endothelial specific deletion of SHP-1 restores VEGF proangiogenic actions and prevents senescence in ischemic muscle and artery of diabetic mice and patients.
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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) | 0.001 | 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 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".