Modulation of the Cochaperone AHA1 Regulates Heat-Shock Protein 90 and Endothelial NO Synthase Activation by Vascular Endothelial Growth Factor
Bibliographic record
Abstract
OBJECTIVE: Vascular endothelial growth factor (VEGF) signaling to endothelial NO synthase (eNOS) plays a central role in angiogenesis. In endothelial cells (ECs), heat-shock protein 90 (Hsp90) is also a regulator of eNOS activity. Our study is designed to determine whether modulation of the activator of Hsp90 ATPase 1 (AHA1) regulates the function of Hsp90 in ECs. METHODS AND RESULTS: We show that eNOS phosphorylation on Ser-1179 after VEGF stimulation is significantly reduced in ECs transfected with a small interfering RNA against AHA1. Accordingly, VEGF-stimulated NO production, endothelial permeability, cell migration, and EC invasion in Matrigel implants in mice are reduced in small interfering RNA against AHA1-treated conditions. Furthermore, the induction of eNOS association with Hsp90 after VEGF stimulation is decreased in AHA1-downregulated cells. We also demonstrate that modulation of Hsp90 activity by AHA1 regulates phosphorylation of Hsp90 on Tyr-300. Interestingly, the association of AHA1 with Hsp90 is increased after c-Src-mediated phosphorylation of Hsp90 on Tyr-300. Finally, we show that overexpression of AHA1 in ECs promotes association of eNOS and Hsp90, phosphorylation of Ser-1179 of eNOS, increases NO production, and cell migration. CONCLUSIONS: These results reveal that modulation of Hsp90 activity by AHA1 regulates VEGF signaling to eNOS and angiogenesis.
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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".