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 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) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.002 |
| 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".