3M03 Soluble fms-like tyrosine kinase 1 (sFlt1) is downregulated in aortic valve stenosis, promoting intravalvular neovascularisation
Bibliographic record
Abstract
Aortic valve stenosis (AVS) is the progressive calcification and loss-of-function of the aortic valve, leading to heart failure, left-ventricular hypertrophy and ultimately death. Despite affecting 3% of the population over 65 years there exists no drug treatment for AVS, leaving invasive surgery as the only option. Critical to the progression of AVS is the neovascularisation of the aortic valve leaflets. This allows for the infiltration of immune cells, such as macrophage and monocytes, into the valve tissue resulting in an inflammatory and proliferative response. The resultant tissue hypoxia stimulates angiogenesis and AVS disease progression. Inhibiting angiogenesis is therefore an attractive potential target for the treatment of AVS. The aim of this study was to determine the role of angiogenesis mediators during aortic valve neovascularisation and the progression of AVS. Human aortic valve tissue was obtained from patients undergoing aortic valve replacement surgery at Aberdeen Royal Infirmary. In vitro techniques were performed using isolated and cultured primary human aortic valve interstitial cells (VICs). Immunohistochemistry of CD31 positive endothelial cells within human aortic valves showed that diseased aortic valves had significantly increased intravalvular vessel number in comparison to healthy aortic valves (control - 3.93±1.25 vessels/mm2versus diseased - 14.93±2.69 vessels/mm2, p<0.01, n=10). Soluble fms-like tyrosine kinase 1 (sFlt1) is a soluble isoform of the VEGF Receptor 1 which acts to inhibit angiogenesis by sequestering VEGF and thereby preventing signalling via the membrane-bound VEGF receptors. Hypoxia (induced by incubation in hypoxic chamber at 1% O2, 5% CO2), which is observed within valve tissue after the onset of AVS progression, reduced the protein expression of sFlt1, whilst increasing VEGF-A expression (0.58±0.13 fold decrease in sFlt1 protein expression compared to normoxic control after 24 hour hypoxia incubation, n=4; 2.26±0.75 fold increase in VEGF-A expression compared to normoxic control after 24 hour hypoxia incubation, n=4). This hypoxia induced modulation in the balance of pro- and anti-angiogenic was able to promote angiogenesis. Conditioned media collected from VICs exposed to hypoxia significantly increased human umbilical vein endothelial cell tubule formation in vitro (42.41%±9.13% increase in tubule formation after 48 hour hypoxia incubation versus normoxic control, p<0.05, n=3). Preliminary data from an siRNA knockdown of sFlt1 on cultured VICs indicate that loss of sFlt1 promotes angiogenesis in vitro using a HUVEC based assay measuring endothelial tubule formation (20.00%±8.21% increase in tubule formation in sFlt1 siRNA knockdown compared to control siRNA, n=2). In summary, this data suggests that sFlt1 is an important factor in maintaining aortic valve avascularity. We have also shown that sFlt-1 reduction is caused by the pathologically relevant environmental changes which occur during the progression of AVS. Together this work highlights the potential of sFlt1 as a therapeutic target in the treatment of AVS via the prevention of intravalvular neovascularisation.
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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 | 0.000 |
| 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".