Ang-(1-7) and ET-1 Interplay Through Mas and ET <sub>B</sub> Receptor Interaction Defines a Novel Vasoprotective Mechanism
Bibliographic record
Abstract
BACKGROUND: Ang-(1-7) (angiotensin (1-7)) via MasR (Mas receptor) opposes vaso-injurious actions of Ang II (angiotensin II) as shown in models of pulmonary hypertension. The underlying mechanisms remain unclear. We hypothesized cross talk between Ang-(1-7) and the protective arm of the ET-1 (endothelin-1) system involving MasR and ET B R (endothelin receptor type B). METHODS: To address this, we studied multiple models: in vivo, in a mouse model of ET-1–associated vascular injury (hypoxia-induced pulmonary hypertension); ex vivo, in isolated mouse arteries; and in vitro, in human endothelial cells. RESULTS: Pulmonary hypertension mice exhibited pulmonary vascular remodeling, endothelial dysfunction, and ET-1–induced hypercontractility. Ang-(1-7) treatment (14 days) ameliorated these effects and increased the expression of vascular ET B R. In human endothelial cells, Ang-(1-7)–induced activation of eNOS (endothelial NO synthase)/NO was attenuated by A779 (MasR antagonist) and BQ788 (ET B R antagonist). A779 inhibited ET-1–induced signaling. Coimmunoprecipitation and peptide array experiments demonstrated the interaction between MasR and ET B R. Binding sites for ET B R were mapped to MasR (amino acids 290–314). Binding sites for MasR on ET B R were identified (amino acids 176–200). Peptides that disrupt MasR:ET B R prevented Ang-(1-7) and ET-1 signaling. Using high-throughput screening, we identified compounds that enhance MasR:ET B R interaction, which we termed enhancers. Enhancers increased Ang-(1-7)–induced eNOS activity, NO production, and Ang-(1-7)–mediated vasorelaxation, and reduced contractile responses. CONCLUSIONS: We identify cross talk between Ang-(1-7) and ET-1 through MasR:ET B R interaction as a novel network that is vasoprotective. Promoting coactivity between these systems amplifies Ang-(1-7) signaling, increases ET-1/ET B R-mediated vascular actions, and attenuates the injurious effects of ET-1. Enhancing Ang-(1-7)/MasR:ET-1/ET B R signaling may have therapeutic potential in conditions associated with vascular damage.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| 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) | 0.000 | 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 teacher head, 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".