title: Vascular function during prolonged progression and regression of atherosclerosis in mice.
abstract: OBJECTIVE
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors: Departments of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA, USA. miller.jordan@mayo.edu
authors: Jordan D
authors: JD
authors: Miller
authors: Yi
authors: Y
authors: Chu
authors: Lauren E
authors: LE
authors: Castaneda
authors: Kristine M
authors: KM
authors: Serrano
authors: Robert M
authors: RM
authors: Brooks
authors: Donald D
authors: DD
authors: Heistad
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001011:Aorta / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology*; D050197:Atherosclerosis / Q000097:blood / Q000209:etiology / Q000235:genetics / Q000503:physiopathology*; D001708:Biopterins / Q000031:analogs & derivatives / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D002784:Cholesterol / Q000097:blood; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology*; D005260:Female; D005786:Gene Expression Regulation; D006937:Hypercholesterolemia / Q000097:blood / Q000150:complications / Q000235:genetics; D007150:Immunohistochemistry; D051379:Mice; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000378:metabolism; D020030:Nitric Oxide Donors / Q000494:pharmacology; D011622:Pterins / Q000378:metabolism; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics; D013762:Tetrahydrofolate Dehydrogenase / Q000378:metabolism; D013997:Time Factors; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D000975:Antioxidants; D002352:Carrier Proteins; D020030:Nitric Oxide Donors; D011622:Pterins; D011973:Receptors, LDL; D014665:Vasodilator Agents; C106092:microsomal triglyceride transfer protein; D001708:Biopterins; D009569:Nitric Oxide; D002784:Cholesterol; C016727:sepiapterin; D013762:Tetrahydrofolate Dehydrogenase; C003402:sapropterin