TIMP3 is the primary TIMP to regulate agonist-induced vascular remodelling and hypertension
Bibliographic record
Abstract
AIMS: Hypertension is accompanied by structural remodelling of vascular extracellular matrix (ECM). Tissue inhibitor of metalloproteinases (TIMPs) inhibits matrix metalloproteinases (MMPs) that degrade the matrix structural proteins. In response to a hypertensive stimulus, the balance between MMPs and TIMPs is altered. We examined the role of TIMPs in agonist-induced hypertension. METHODS AND RESULTS: We subjected TIMP-knockout mice to angiotensin II (Ang II) infusion, and found that Ang-II-induced hypertension in TIMP1(-/-), TIMP2(-/-), and TIMP4(-/-) mice was comparable to wild-type (WT) mice, but significantly suppressed in TIMP3(-/-) mice. Ex vivo pressure myography analyses on carotid and mesenteric arteries revealed that Ang-II-infused TIMP3(-/-) arteries were more distensible with impaired elastic recoil compared with the WT group. The acute response to vasoconstriction and vasodilation was intact in TIMP3(-/-) mesenteric and carotid arteries. Mesenteric arteries from TIMP3(-/-)-Ang II mice exhibited a reduced media-to-lumen ratio, suppressed collagen and elastin levels, elevated elastase and gelatinase proteolytic activities compared with WT-Ang II. TIMP3(-/-)-Ang II carotid arteries also showed adverse structural remodelling. Treatment of mice with doxycycline, a matrix metalloproteinase inhibitor, improved matrix integrity in mesenteric and carotid arteries in TIMP3(-/-)-Ang II and differentially regulated elastin and collagen levels in WT-Ang II vs. TIMP3(-/-)-Ang II. CONCLUSION: Our study demonstrates a critical role for TIMP3, among all TIMPs, is preserving arterial ECM in response to Ang II. It is critical to acknowledge that the suppressed Ang-II-induced hypertension in TIMP3(-/-) mice is not a protective mechanism but owing to adverse remodelling in arterial matrix.
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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) | 0.000 | 0.001 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.004 | 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".