Abstract FR611: Vascular Smooth Muscle Cell Notch3 Modulates Brown Adipose Tissue Inflammation and Effects on Contraction Through Nox4
Bibliographic record
Abstract
We previously demonstrated that VSMCs Notch3 regulates brown adipose tissue (BAT) production of adiponectin and anti-contractile effects. Nox4-derived H2O2 is involved in BAT protective effects in the vasculature. Here, we investigated whether Nox4 plays a role in Notch3 regulation of BAT biology and if the Notch3/Nox4 vascular-BAT interactome is altered in hypertension. We characterized Notch3 signaling in BAT from Nox4 KO mice (N4KO). We evaluated expression of Notch3 and its intracellular domain (activation), BAT markers (UCP-1, IL-6), adiponectin and markers of inflammation (CD45, TNFα) and fibrosis (Col1A1, IL-11, galectin-3) by qPCR and WB. Isolated arteries from control mice were exposed to BAT conditioned medium (CM) and vascular function assessed by myography. Expression of Notch3 (N4KO: 0.60±0.01; WT: 1.06±0.02 AU, p<0.05) and its ICD (N4KO: 0.55±0.008; WT: 0.72±0.01 AU, p<0.05) were reduced in Nox4 KO BAT; followed by reduced expression of UCP-1 (N4KO: 0.72±0.04; WT: 1.05±0.06 AU, p<0.05) and gene levels of IL-6 (N4KO: 0.56±0.04; WT: 1.31±0.18 2^-ddCt, p<0.05). We did not observe an increase in adiponectin levels in BAT from Nox4 KO. BAT from Nox4 KO mice demonstrated increased levels of pro-inflammatory/fibrotic markers: CD45 (N4KO: 2.55±0.17; WT: 1.0±0.02 2^-ddCt, p<0.05); IL-11 (N4KO: 1.34±0.06; WT: 1.01±0.08 2^-ddCt, p<0.05) and galectin-3 (N4KO: 7.1±0.19; WT: 1.01±0.06 2^-ddCt, p<0.05). The anti-contractile effect of BAT CM was blunted in Nox4 KO conditions. Similar phenotype was found in BAT from LinA3 mice, an Ang II-dependent experimental model of hypertension, where Notch3/Notch3 ICD expression was not altered, followed by an increase pro-inflammatory/fibrotic markers and no changes in BAT markers expression (p<0.05 vs. WT). Nox4 plays an important role in Notch3 regulation of BAT biology, including production of adiponectin and expression of BAT markers. Blunted Notch3/Nox4 axis in adipose tissue during hypertension may lead to BAT dysfunction, inflammation and fibrosis, impacting vascular function and structure. These novel findings suggest an important role for Notch3 in the vascular:adipose interactome in health and cardiovascular diseases.
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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) | 0.000 | 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 | 0.001 |
| Insufficient payload (model declined to judge) | 0.005 | 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".