Abstract 334: Selective Pharmacological Kinin Receptor Activation Restores Postischemic Neovascularisation And Hindlimb Perfusion In Diabetic Mice
Bibliographic record
Abstract
Limb ischemia (LI) is a major complication of several cardiovascular diseases. Hyperglycaemia worsens LI by impairing neovascularisation. Genetic or pharmacological inactivation of the kallikrein-kinin system aggravates LI experimentally while ACE/kininase II inhibition improves its outcome. We assessed whether direct, selective and potent pharmacological activation of kinin receptors, B1 or B2, can have therapeutic effect in mice with LI. The selective B1 receptor agonist SarLys[Hyp3,Igl5,DPhe8]desArg9-bradykinin (B1-ago) or the selective B2 agonist [Hyp(3),Thi(5),(N)Chg(7),Thi(8)]-bradykinin (B2-ago) were administered by osmotic micropumps (30 nmole/kg.h-1) for 14 days after unilateral femoral artery ligature in mice previously rendered diabetic by streptozotocin. Comparison was made with ligatured, non-agonist treated normoglycaemic (normo) and hyperglycaemic (control-hyper) mice. Chronic administration of B2-ago had no effect on blood pressure, like B1-ago. B1-ago or B2-ago similarly restored the impaired neovascularisation process in diabetic mice as assessed by microangiography [angiographic score, ischemic/non-ischemic hindlimb ratio (R) 0.99±0.13, 0.60±0.06, 1.09±0.13 and 0.99±0.07 in normo, control-hyper, B1-ago and B2-ago respectively, n=10/group, p<0.01] and by histological capillary density analysis (R: 1.2±0.2, 0.68±0.04, 1.7±0.1, and 1.8±0.1, p<0.01). Both treatments increased blood flow in the ischemic hindfoot measured by laser doppler perfusion imaging (R: 0.62±0.05, 0.47±0.03, 0.76±0.04, 0.69±0.03 in normo, control-hyper, B1-ago and B2-ago respectively, p<0.01). VEGF content in the ischemic gastrocnemius muscle increased 2 fold (p<0.05) during B1-ago or B2-ago treatment and macrophage infiltration 3 fold (p<0.01). Both treatments increased (0.5 to 1 fold, p<0.05) circulating CD45/CD 11b-positive monocytes and CD34/VEGFR2 endothelium or bone marrow derived progenitor cells but not other bone marrow derived progenitors. Thus, selective pharmacological activation of either B1 or B2 receptor restores postischemic neovascularisation and tissue perfusion in hyperglycaemic mice. This effect involves mobilisation of macrophages and enhanced VEGF synthesis.
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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) | 0.001 | 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".