Abstract 14787: Loss of Wnt7a is Associated With Reduced Vegf-a/vegfr2 Mediated Endothelial Tip Cell Formation and Angiogenesis in Pulmonary Arterial Hypertension
Bibliographic record
Abstract
Rationale: Pulmonary arterial hypertension (PAH) is characterized by loss of microvessels. The Wnt pathways control pulmonary angiogenesis but their role in PAH is incompletely understood. Objective: We hypothesized that Wnt activation in pulmonary microvascular endothelial cells (PMVECs) is required for pulmonary angiogenesis and its loss contributes to PAH. Methods: Lung tissue and PMVECs from healthy donors and PAH patients were screened for Wnt ligand production. Tip cell dynamics were analyzed using 3D spheroid assays and in vivo studies were carried out with tamoxifen-inducible Wnt knockout mice exposed to chronic hypoxia and Sugen-hypoxia (SuHx). Results: Healthy PMVECs demonstrated ~6-fold Wnt7a expression that was absent in PAH PMVECs and vascular lesions. Wnt7a expression correlated with formation of tip cells, an endothelial phenotype critical for angiogenesis. To analyze PMVEC tip cell formation, we developed a 3D PMVEC spheroid model combined with live imaging to monitor the behavior of healthy and PAH PMVECs in response to VEGF-A and Wnt7a. We found that PAH PMVECs demonstrated reduced tip cell formation as evidenced by reduced filopodia formation and random motility, which could be partially rescued by recombinant Wnt7a. The mechanism by which Wnt7a promotes VEGF signaling activity is dependent on its capacity to activate the small GTPase cdc42 and facilitate phosphorylation of the Y951 and Y1175 tyrosine residues in VEGFR2 following VEGF-A stimulation. While there was no phenotypic difference between wild type and mice with endothelial-specific Wnt7a knockout (Wnt7a EC/EC ) under chronic hypoxia and SuHx, we found that global Wnt7a +/- mice demonstrated higher pressures and vascular remodeling compared to wild type mice. Interestingly, we found that global Wnt7a knockout (Wnt7a KO/KO ) mice succumbed 10 days after tamoxifen injection demonstrating interstitial thickening associated with expansion of the pulmonary capillaries, an unexpected phenotype resembling alveolar capillary dysplasia. Conclusions: We have identified Wnt7a as a novel angiogenic factor that plays a pivotal role in pulmonary angiogenesis by promoting VEGF-A mediated tip cell formation. Targeting Wnt7a could promote recovery of small vessel loss in PAH.
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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) | 0.006 | 0.002 |
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".