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Atorvastatin restores endothelial function in offspring of protein-restricted rats in a cholesterol-independent
Christopher Torrens1, Christopher J Kelsall, Laura A Hopkins
1Vascular Biology Group, Institute of Developmental Sciences (887), University of Southampton, School of Medicine, Southampton General Hospital, Tremona Rd, Southampton S016 6YD, United Kingdom. c.torrens@southampton.ac.uk.
Insights
Maternal protein restriction impairs offspring vascular function. Atorvastatin (a statin) corrected this endothelial dysfunction in mesenteric arteries, but effects varied by gender and blood vessel type.
Area of Science:
- Cardiovascular Physiology
- Developmental Biology
- Pharmacology
Background:
- Maternal protein restriction during pregnancy can cause endothelial dysfunction and reduced nitric oxide (NO) bioavailability in offspring.
- Statins, such as atorvastatin, possess pleiotropic effects, including enhanced NO bioavailability and anti-inflammatory properties.
- This study investigates the impact of atorvastatin on vascular function in offspring exposed to maternal protein restriction, independent of dyslipidemia.
Purpose of the Study:
- To evaluate the efficacy of atorvastatin in ameliorating endothelial dysfunction in offspring of protein-restricted rats.
- To determine if atorvastatin treatment affects inflammatory markers in this model.
- To assess gender-specific and vascular bed-specific responses to atorvastatin.
Main Methods:
- Wistar rats were fed control or protein-restricted diets throughout pregnancy.
- Offspring from protein-restricted dams received atorvastatin from weaning.
- Vascular reactivity of thoracic aorta and mesenteric arteries was assessed using wire myography; plasma inflammatory markers and gene expression were analyzed.
Main Results:
- Endothelial-dependent vasodilation was reduced in thoracic aortas of male offspring but not females.
- Mesenteric artery vasodilation was impaired in both male and female offspring but restored by atorvastatin.
- Atorvastatin normalized C-reactive protein in female offspring but had no effect on inflammatory markers in males.
Conclusions:
- Atorvastatin can restore endothelial function in mesenteric arteries of offspring affected by maternal protein restriction.
- The therapeutic effects of atorvastatin are gender-specific and depend on the specific vascular bed.
- These findings highlight the potential of statins in managing developmental programming of vascular dysfunction.
Abstract:
Maternal protein restriction in rats leads to endothelial dysfunction and decreased NO bioavailability in the offspring. Statins (3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors) are recognized to have pleiotropic actions including increasing NO bioavailability and reducing inflammation and oxidative damage. This study assessed statin treatment on vascular function in a model of endothelial dysfunction, which is independent of dyslipidemia. Wistar rats were fed a control (18% casein) or protein-restricted (9% casein) diet throughout pregnancy. At weaning, a subset of the protein-restricted group was given atorvastatin (10 mg/kg per day) in the drinking water. At 145 days of age, offspring were euthanized by CO(2) inhalation. Plasma samples were collected for markers of inflammation, vascular reactivity of the thoracic aorta, and small mesenteric arteries were assessed on the wire myograph, and tissues were snap frozen for molecular biology analysis. Thoracic aorta endothelial-dependent vasodilatation was attenuated in the male offspring from both protein-restricted groups compared with controls (P<0.05) but was similar in females (P value not significant). Endothelial-dependent dilatation of mesenteric arteries was attenuated in male and female protein-restricted offspring (P<0.05) and was corrected by atorvastatin. Maternal protein restriction increased plasma inflammatory markers granulocyte chemotactic protein, lipocalin-2, and beta(2)-microglobulin in male and C-reactive protein in female offspring (P<0.05). Atorvastatin had no effect on inflammatory markers in the males but restored C-reactive protein to control levels in the females (P<0.05). Aortic and mesenteric artery mRNA levels of endothelial NO synthase, superoxide dismutase 1, and tumor necrosis factor-alpha were unchanged. These data suggest that atorvastatin can restore endothelial function in this model, but its effects are gender specific and dependent on the vascular bed.
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