ANGPTL6 variant induces cerebral vascular dysfunction and predisposes to intracranial aneurysm in mice
Bibliographic record
Abstract
Abstract Background Intracranial aneurysm (IA) is a common cerebrovascular abnormality characterized by localized dilation and wall thinning in intracranial arteries, that frequently leads to fatal sub-arachnoid hemorrhage. Pathophysiological mechanisms responsible for AI remains largely unknown, but increasing evidence suggest that genetic susceptibility plays a predominant role. We recently identified a rare nonsense variant in ANGPTL6 gene that prevented angiopoietin-like 6 (ANGPTL6) secretion and predisposed to IA. The aim of this study is now to understand why the ANGPTL6 variant predisposes to IA. Methods Angptl6 -knock in mice were generated by homologous recombination. Cerebral arteries of the circle of Willis have been analyzed under basal and hemodynamic overload conditions. Functional properties of cerebral arteries have been analyzed by pressure arteriography. Effect of recombinant ANGPTL6 have been assessed on vascular smooth muscle cells and ANGPTL6 partners have been analyzed by surface plasmon resonance. Results Angptl6 -knock in mice display endothelial dysfunction expressed by reduced NO production in response to flow in cerebral arteries. They present exaggerated dilatation of cerebral arteries under hypertensive stress, and aggravated wall damage and aneurysmal remodeling of the intima and media at arterial bifurcations of the circle of Willis under hemodynamic overload. Matrix bound ANGPTL6 decreased VSMC migration and increased adhesion and FAK signaling activation, without affecting VSMC phenotype. Surface plasmon resonance analyses identified αvβ5 integrin as a new ANPTL6 receptor. Conclusions Angptl6 -knock in mice mimicked the main features of IA in humans. ANGPTL6 appears to be an extracellular matrix component regulating vascular cell function, which may be involved in mechanosensing and generating adapted vascular cell responses to hemodynamic stress. Non-secreted ANGPTL6 variants would result in the loss of this function, thus favoring IA under conditions of hemodynamic overload.
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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 | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.003 | 0.001 |
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".