PS-BPB04-7: PRO-ANGIOGENIC EFFECTS OF LSKL, A THROMBOSPONDIN-1 INHIBITOR, IN HUMAN AND EXPERIMENTAL MODELS OF PREECLAMPSIA
Bibliographic record
Abstract
Introduction: Preeclampsia (PE) is a hypertensive disorder of pregnancy characterized by blood pressure above 140/90 mmHg. It accounts for 10% of all pregnancies and is responsible for 25% of preterm births and low birth weight. To date, no medications can treat or prevent PE. We identified an activation of the anti-angiogenic protein thrombospondin-1 (THBS1) in human and experimental preeclampsia. THBS1 is also a main activator of TGF-β. We postulate that THBS1-mediated TGF-β activation may contribute to impair placental angiogenesis during PE. Objective: We aimed to test the effects of LSKL, an inhibitor of THBS1-mediated TGF-β activation, on angiogenesis in placentas of a mouse model of PE and in human placental endothelial cells. Methods: Peptide LSKL or its control peptide SLLK (280 μM in 0.5 ml saline, s.c.) was administered at gestational day (GD) 14.5 in heterozygous transgenic mice overexpressing human renin and human angiotensinogen and controls (C57BL/6). Placentas (n = 12/group) were removed at GD 18.5. Protein expression of TGF-β1, TGF-β2, total and phosphorylated SMAD2 were assessed by western blot of placental lysates. Placental angiogenesis was assessed by CD31+ immunohistochemistry in placental sections. CD31+ endothelial cells were extracted by magnetic sorting from human placentas (n = 4) of healthy pregnancies. Cells (2–5 passages) were treated with LSKL or SLLK (30 μM) under hypoxia (0.5% vs. 8% O2) or thrombin (10 u/mL) exposure (4 hours). THBS1 expression in placental endothelial cells was assessed by immunofluorescence. Cell angiogenesis was quantified by the number of closed tubes formed on matrigel (per 15,000 cells, 4 hours). Results: Maternal LSKL treatment significantly reduced the expression of TGF-β2 (P < 0.01) and SMAD2 phosphorylation (P < 0.05) while improving angiogenesis (P < 0.05) in placentas of transgenic preeclamptic mouse compared to controls. In human placental endothelial cells, both thrombin (P < 0.05) and hypoxia (P < 0.05) significantly increased THBS1 expression. Thrombin (P < 0.01) and hypoxia (P < 0.05) significantly impaired cell angiogenesis on matrigel (P < 0.01), which was prevented by LSKL treatment (P < 0.01). In human cells, LSKL similarly reduced TGB-β2 (p < 0.05) and phospho-SMAD2 (P < 0.05) expressions under thrombin and hypoxia cell exposure. Conclusion: Our results describe a significant pro-angiogenic effect of LSKL treatment by regulating THBS1 and TGF-β2 mechanisms in human and experimental models of PE.
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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) | 0.001 | 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 | 0.000 |
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".