Toll-like receptor 4 activation contributes to systemic vascular dysfunction in pregnant rats fed a high cholesterol diet during pregnancy
Bibliographic record
Abstract
Background: Hypercholesterolemia is a hallmark clinical feature of cardiovascular diseases. Vascular adaptations to pregnancy include withstanding pregnancy-induced hypercholesterolemia, a physiological process required for fetus development. However, excessive (pathological) hypercholesterolemia during pregnancy has been linked to an increased risk of complications (e.g., preeclampsia); still, the underlying mechanisms are unclear. Toll-like receptor 4 (TLR4) is an innate immune receptor modulated by high cholesterol levels (in non-pregnant animals), but whether TLR4 activation also plays a role in vascular dysfunction in pregnancies complicated with hypercholesterolemia is unknown. Hypothesis: Pathological hypercholesterolemia during pregnancy causes maternal vascular dysfunction via activation of TLR4. Methods: Sprague Dawley rats were fed a standard (CD) or high cholesterol diet (HCD; 2% cholesterol and 0.5% cholic acid) from gestational day (GD) 6 to GD20 (term=22 days; n=9-10). Blood pressure was assessed before pregnancy and on GD19, and the results are presented as delta change. On GD20, body weight and pregnancy outcomes were recorded, and mesenteric arteries (systemic resistance arteries) were assessed using wire myography to evaluate vasoconstriction capacity to phenylephrine and endothelial-dependent vasodilation responses to methacholine. Experiments were conducted in the presence or absence of L-NAME (a pan-NOS inhibitor, 100 mmol/l) and/or CLI-095 (a TLR4 inhibitor, 10 mmol/l). Functional data were summarized as Emax (maximum response) or pEC50 (concentration required to produce 50% of Emax). Statistics: Student’s t-test or two-way ANOVA with Sidak post hoc test (significance: p<0.05). Results: The HCD prevented the late gestation systolic (p=0.0004) and diastolic (p=0.0066) blood pressure reduction observed in the CD group, and impaired male (p=0.0062) and female (p=0.0352) fetoplacental efficiency. Total body weight gain during pregnancy was not different between CD and HCD dams (p>0.05). In mesenteric arteries, vasoconstriction responses to phenylephrine (Emax) were increased in HCD dams (p=0.0056), and TLR4 inhibition with CLI-095 reduced the sensitivity (pEC50) of phenylephrine in these vessels (p=0.0147). Additionally, HCD dams presented higher sensitivity (pEC50) to methacholine (p=0.0169), which was not modified by the TLR4 inhibitor (p>0.05). Incubation of arteries with L-NAME abolished the increased sensitivity to methacholine (p>0.05), which was not further altered by CLI-095 (p>0.05). Conclusion: Inhibition of TLR4 ( ex vivo) reduced the enhanced vasoconstriction observed in HCD dams but did not alter endothelial-dependent vasodilation responses. Thus, if inhibiting TLR4 could block the vasoconstrictor effects of excessive hypercholesterolemia during pregnancy, this may be a target for future therapy development. This work was supported by a foundation grant from CIHR (FS154313) and by the generosity of the Stollery Children's Hospital Foundation and the Alberta Women's Health Foundation through the Women and Children's Health Research Institute (WCHRI). This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
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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) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.001 |
| 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".