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      Impaired Vasorelaxation in Inbred Mice Is Associated with Alterations in Both Nitric Oxide and Super Oxide Pathways

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          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 (∼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.

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          Most cited references 24

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          Hypertension in mice lacking the gene for endothelial nitric oxide synthase.

          Nitric oxide (NO), a potent vasodilator produced by endothelial cells, is thought to be the endothelium-dependent relaxing factor (EDRF) which mediates vascular relaxation in response to acetylcholine, bradykinin and substance P in many vascular beds. NO has been implicated in the regulation of blood pressure and regional blood flow, and also affects vascular smooth-muscle proliferation and inhibits platelet aggregation and leukocyte adhesion. Abnormalities in endothelial production of NO occur in atherosclerosis, diabetes and hypertension. Pharmacological blockade of NO production with arginine analogues such as L-nitroarginine (L-NA) or L-N-arginine methyl ester affects multiple isoforms of nitric oxide synthase (NOS), and so cannot distinguish their physiological roles. To study the role of endothelial NOS (eNOS) in vascular function, we disrupted the gene encoding eNOS in mice. Endothelium-derived relaxing factor activity, as assayed by acetylcholine-induced relaxation, is absent, and the eNOS mutant mice are hypertensive. Thus eNOS mediates basal vasodilation. Responses to NOS blockade in the mutant mice suggest that non-endothelial isoforms of NOS may be involved in maintaining blood pressure.
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            Dilated cardiomyopathy and neonatal lethality in mutant mice lacking manganese superoxide dismutase.

            The Sod2 gene for Mn-superoxide dismutase (MnSOD), an intramitochondrial free radical scavenging enzyme that is the first line of defense against superoxide produced as a byproduct of oxidative phosphorylation, was inactivated by homologous recombination. Homozygous mutant mice die within the first 10 days of life with a dilated cardiomyopathy, accumulation of lipid in liver and skeletal muscle, and metabolic acidosis. Cytochemical analysis revealed a severe reduction in succinate dehydrogenase (complex II) and aconitase (a TCA cycle enzyme) activities in the heart and, to a lesser extent, in other organs. These findings indicate that MnSOD is required for normal biological function of tissues by maintaining the integrity of mitochondrial enzymes susceptible to direct inactivation by superoxide.
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              Direct evidence for the importance of endothelium-derived nitric oxide in vascular remodeling.

              The vascular endothelium mediates the ability of blood vessels to alter their architecture in response to hemodynamic changes; however, the specific endothelial-derived factors that are responsible for vascular remodeling are poorly understood. Here we show that endothelial-derived nitric oxide (NO) is a major endothelial-derived mediator controlling vascular remodeling. In response to external carotid artery ligation, mice with targeted disruption of the endothelial nitric oxide synthase gene (eNOS) did not remodel their ipsilateral common carotid arteries whereas wild-type mice did. Rather, the eNOS mutant mice displayed a paradoxical increase in wall thickness accompanied by a hyperplastic response of the arterial wall. These findings demonstrate a critical role for endogenous NO as a negative regulator of vascular smooth muscle proliferation in response to a remodeling stimulus. Furthermore, our data suggests that a primary defect in the NOS/NO pathway can promote abnormal remodeling and may facilitate pathological changes in vessel wall morphology associated with complex diseases such as hypertension and atherosclerosis.

                Author and article information

                J Vasc Res
                Journal of Vascular Research
                S. Karger AG
                October 2007
                30 July 2007
                : 44
                : 6
                : 504-512
                Cardiovascular Research Institute, Department of Medicine, University of Rochester, Rochester, N.Y., USA
                106751 J Vasc Res 2007;44:504–512
                © 2007 S. Karger AG, Basel

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                Page count
                Figures: 4, Tables: 1, References: 38, Pages: 9
                Research Paper


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