Abstract P220: Matrix Metalloproteinase 2 Knockout Protects from Angiotensin II-induced Vascular Injury
Bibliographic record
Abstract
Objective: Matrix metalloproteinase-2 (MMP2) participates in the mechanisms of vascular injury in atherosclerosis. Whether MMP2 plays a role in angiotensin (Ang) II-induced hypertension and vascular remodeling is unknown. We hypothesized that Mmp2 knockout ( Mmp2 -/- ) would prevent Ang II-induced hypertension and vascular injury. Methods and Results: Fourteen days of Ang II infusion (1000 ng/kg/min, SC) increased systolic blood pressure (SBP, 161±9 vs 122±3 mm Hg, P <0.05) and decreased vasodilatory responses to acetylcholine (33±5 vs 83±3%, P <0.001), increased the media/lumen (4.8±0.4 vs 3.1±0.1%, P <0.001) and media cross-sectional area (7223±467 vs 5346±336 μm 2 , P <0.05) and enhanced stiffness ( P <0.05), as shown by a leftward shift of the stress/strain relationship of mesenteric arteries in wild-type mice. Ang II enhanced aortic (73±6 vs 6±1 relative fluorescence units [RFU]/μm 2 , P <0.001) and perivascular adipose tissue (PVAT) reactive oxygen species generation (76±11 vs 12±1 RFU/μm 2 , P <0.001), aortic VCAM-1 (17±3 vs 5±1 RFU/μm 2 , P <0.001) and MCP-1 expression (71±14 vs 11±3 RFU/μm 2 , P <0.001), PVAT monocyte/macrophage (1.8±0.3 vs 0.1±0.1 % of PVAT, P <0.001) and T cell infiltration (56±14 vs 16±9 cells/μm 2 , P <0.05) and the fraction of spleen activated CD4 + CD69 + (17±2 vs 10±1 % of CD4+ T cells, P <0.001), CD8 + CD69 + T cells (11±1 vs 5±1 % of CD4+ T cells, P <0.001) and Ly-6C hi monocytes (53±6 vs 25±2 % event, P <0.001). Ang II increased phosphorylation of epidermal growth factor receptor 1.9±0.2-fold and extracellular-signal-regulated kinase 1/2 1.4±0.1-fold in vascular smooth muscle cells isolated from mesenteric arteries of wild-type mice ( P <0.05). Mmp2 knockout prevented or reduced all of the above ( P <0.05) except SBP elevation. Bone marrow transplantation experiments revealed that Ang II-induced hypertension was impaired in absence of immune cell MMP2 and endothelial dysfunction was blunted or reduced in absence of immune or vascular cell MMP2 ( P <0.05). Conclusions: Mmp2 knockout prevented Ang II-induced vascular injury but not hypertension. Bone marrow transplantation experiments revealed a complex relationship of immune and vascular cell MMP2 in the development of Ang II-induced hypertension and endothelial dysfunction.
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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) | 0.001 | 0.001 |
| 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".