Impaired vasorelaxation in inbred mice is associated with alterations in both nitric oxide and super oxide pathways.
Recently, we showed that genetic factors determine flow-dependent vascular remodeling. Among five inbred mouse strains, the SJL strain developed the largest intima in response to low flow. Because SJL mice have a spontaneous mutation in superoxide dismutase 2 (SOD-2) we tested the hypothesis that strain-specific variations in vascular function are due to alterations in redox and nitric oxide (NO) pathways. Vasorelaxation to acetylcholine was significantly impaired in aortic rings from SJL compared to C3H or FVB mice (up to 40%). Relaxation to the endothelium-independent vasodilator sodium nitroprusside (SNP) in SJL mice was also significantly impaired at low concentrations, with decreases in sensitivity and maximal relaxation to SNP compared to C3H and FVB mice. Western blot analyses showed significantly decreased expression (approximately 40%) of eNOS, PKG and SOD-2 proteins in SJL vasculature compared to C3H. Intact aortas from SJL showed significantly increased nitrotyrosine and decreased SOD-2 expression compared to C3H by immunohistochemistry. Basal levels of superoxide in aortas from SJL were not significantly different than C3H as measured by dihydroethidine. In summary, relatively small alterations in redox (SOD-2) and NO pathways (eNOS and PKG) may contribute to significantly impaired vasorelaxation in SJL mice.
Cardiovascular Research Institute, Department of Medicine, University of Rochester, Rochester, NY 14642, USA. Bradford_Berk@URMC.rochester.edu
Chun
C
Chen
Vyacheslav A
VA
Korshunov
Michael P
MP
Massett
Chen
C
Yan
Bradford C
BC
Berk
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism* / Q000503:physiopathology; D017869:Cyclic GMP-Dependent Protein Kinases / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism* / Q000503:physiopathology; D066298:In Vitro Techniques; D051379:Mice; D008809:Mice, Inbred C3H; D008815:Mice, Inbred Strains; D009569:Nitric Oxide / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III; D009599:Nitroprusside / Q000494:pharmacology; D010084:Oxidation-Reduction; D010656:Phenylephrine / Q000494:pharmacology; D011189:Potassium Chloride / Q000494:pharmacology; D013045:Species Specificity; D013482:Superoxide Dismutase / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism*; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism; D014661:Vasoconstriction; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology; D000099156:Superoxide Dismutase 2
D000109:Acetylcholine; D017869:Cyclic GMP-Dependent Protein Kinases; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D009599:Nitroprusside; D010656:Phenylephrine; D011189:Potassium Chloride; D013482:Superoxide Dismutase; D013481:Superoxides; D014443:Tyrosine; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; D000099156:Superoxide Dismutase 2; C002744:3-nitrotyrosine; C496315:Nos3 protein, mouse