Vascular function during prolonged progression and regression of atherosclerosis in mice

Jordan D Miller; Yi Chu; Lauren E Castaneda; Kristine M Serrano; Robert M Brooks; Donald D Heistad

doi:10.1161/ATVBAHA.112.252700

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Vascular function during prolonged progression and regression of atherosclerosis in mice

Journal article

Open access

Peer reviewed

Vascular function during prolonged progression and regression of atherosclerosis in mice

Jordan D Miller, Yi Chu, Lauren E Castaneda, Kristine M Serrano, Robert M Brooks and Donald D Heistad

Arteriosclerosis, thrombosis, and vascular biology, Vol.33(3), pp.459-465

03/2013

DOI: 10.1161/ATVBAHA.112.252700

PMCID: PMC3960951

PMID: 23307875

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https://doi.org/10.1161/ATVBAHA.112.252700View

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Abstract

Endothelial dysfunction is associated with atherosclerosis in mice, but it is difficult to reduce cholesterol levels enough to study regression of atherosclerosis in genetically modified mice. The goal of this study was to examine vascular structure and function before and after reducing elevated plasma lipid levels with a genetic switch in Reversa mice, and identify novel mechanisms contributing to structural and functional improvements in the vasculature after reduction of blood lipids. After 6 months of hypercholesterolemia, endothelial function (maximum relaxation to acetylcholine) in aorta was impaired and responses to nitric oxide were unaffected. Further impairment in endothelial function was observed after 12 months of hypercholesterolemia and was associated with reductions in sensitivity to nitric oxide. Expression of dihydrofolate reductase was reduced at 6 and 12 months, and addition of the tetrahydrobiopterin precursor sepiapterin significantly improved endothelial function. Reducing cholesterol levels at 6 months normalized dihydrofolate reductase expression and prevented further impairment in endothelial function. Similar functional changes were observed after 12 months of hypercholesterolemia followed by 2 months of lipid lowering. Our data suggest that endothelial dysfunction after prolonged hypercholesterolemia is the result of both impairment of sensitivity to nitric oxide and reduced nitric oxide synthase cofactor bioavailability. Both of these changes can be prevented by normalizing blood lipids during moderately severe or advanced atherosclerosis.

Immunohistochemistry

Pterins - metabolism

Atherosclerosis - genetics

Cholesterol - blood

Endothelium, Vascular - drug effects

Aorta - metabolism

Biopterin - analogs & derivatives

Biopterin - metabolism

Dose-Response Relationship, Drug

Atherosclerosis - etiology

Time Factors

Receptors, LDL - deficiency

Female

Aorta - physiopathology

Nitric Oxide Donors - pharmacology

Disease Models, Animal

Receptors, LDL - genetics

Hypercholesterolemia - blood

Vasodilator Agents - pharmacology

Atherosclerosis - physiopathology

Aorta - drug effects

Endothelium, Vascular - physiopathology

Gene Expression Regulation

Antioxidants - pharmacology

Mice, Knockout

Tetrahydrofolate Dehydrogenase - metabolism

Atherosclerosis - blood

Carrier Proteins - genetics

Animals

Carrier Proteins - metabolism

Endothelium, Vascular - metabolism

Hypercholesterolemia - complications

Mice

Hypercholesterolemia - genetics

Vasodilation - drug effects

Nitric Oxide - metabolism

Details

Title: Subtitle: Vascular function during prolonged progression and regression of atherosclerosis in mice
Creators: Jordan D Miller - Departments of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA, USA. miller.jordan@mayo.edu
Yi Chu
Lauren E Castaneda
Kristine M Serrano
Robert M Brooks
Donald D Heistad
Resource Type: Journal article
Publication Details: Arteriosclerosis, thrombosis, and vascular biology, Vol.33(3), pp.459-465
Publisher: United States
DOI: 10.1161/ATVBAHA.112.252700
PMID: 23307875
PMCID: PMC3960951
ISSN: 1079-5642
eISSN: 1524-4636
Grant note: P01 NS024621 / NINDS NIH HHS NS024621 / NINDS NIH HHS HL092235 / NHLBI NIH HHS P01 HL062984 / NHLBI NIH HHS HL062984 / NHLBI NIH HHS R00 HL092235 / NHLBI NIH HHS K99 HL092235 / NHLBI NIH HHS
Language: English
Date published: 03/2013
Academic Unit: Cardiovascular Medicine; Neuroscience and Pharmacology; Internal Medicine
Record Identifier: 9984040448802771

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