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    Impaired Nitric Oxide Mediated Vasodilation In The Peripheral Circulation In The R6/2 Mouse Model Of Huntington’s Disease

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        Abstract

        Recent evidence shows that the Huntington’s disease (HD) extends beyond the nervous system to other sites, including the cardiovascular system. Further, the cardiovascular pathology pre-dates neurological decline, however the mechanisms involved remain unclear. We investigated in the R6/2 mouse model of HD nitric oxide (NO) dependent and independent endothelial mechanisms. Femoral artery reactivity was determined by wire myography in wild type (WT) and R6/2 mice at 12 and 16 weeks of adulthood. WT mice showed increased endothelial relaxation between 12 and 16 weeks (Rmax: 72 ± 7% vs. 97 ± 13%, P < 0.05). In contrast, R6/2 mice showed enhanced endothelial relaxation already by 12 weeks (Rmax at 12w: 72 ± 7% vs. 94 ± 5%, WT vs. R6/2, P < 0.05) that declined by 16 weeks compared with WT mice (Rmax at 16w: 97 ± 13% vs. 68 ± 7%, WT vs. R6/2, P < 0.05). In WT mice, the increase in femoral relaxation between 12 and 16 weeks was due to enhanced NO dependent mechanisms. By 16 weeks of adult age, the R6/2 mouse developed overt endothelial dysfunction due to an inability to increase NO dependent vasodilation. The data add to the growing literature of non-neural manifestations of HD and implicate NO depletion as a key mechanism underlying the HD pathophysiology in the peripheral vasculature.

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        Most cited references 33

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        Exon 1 of the HD gene with an expanded CAG repeat is sufficient to cause a progressive neurological phenotype in transgenic mice.

         Peter S W Davies,  Holli Harper,  Y Trottier … (1996)
        Huntington's disease (HD) is one of an increasing number of neurodegenerative disorders caused by a CAG/polyglutamine repeat expansion. Mice have been generated that are transgenic for the 5' end of the human HD gene carrying (CAG)115-(CAG)150 repeat expansions. In three lines, the transgene is ubiquitously expressed at both mRNA and protein level. Transgenic mice exhibit a progressive neurological phenotype that exhibits many of the features of HD, including choreiform-like movements, involuntary stereotypic movements, tremor, and epileptic seizures, as well as nonmovement disorder components. This transgenic model will greatly assist in an eventual understanding of the molecular pathology of HD and may open the way to the testing of intervention strategies.
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          Contractile properties of small arterial resistance vessels in spontaneously hypertensive and normotensive rats.

           W Halpern,  M J Mulvany (1977)
          Article 0 comments Cited 123 times – based on 0 reviews     Review now
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            Beyond the brain: widespread pathology in Huntington's disease.

             Jorien MM van der Burg,  Maria Bjorkqvist,  Patrik Brundin (2009)
            Huntington's disease (HD) is an inherited neurodegenerative disorder caused by a polyglutamine stretch in the huntingtin protein. Today, more than 15 years after the genetic defect underlying HD was discovered, the pathogenesis is still not well understood and there is no adequate treatment. Research into this disorder has conventionally focused on neurological symptoms and brain pathology, particularly neurodegeneration in the basal ganglia and cerebral cortex. Mutant huntingtin is, however, ubiquitously expressed throughout the body. Indeed, contrary to earlier thinking, HD is associated with abnormalities in peripheral tissues. These abnormal changes are not all secondary to brain dysfunction, but most seem to be directly caused by expression of mutant huntingtin in peripheral tissues. In this article, we highlight this emerging field of research and how it might affect our understanding of the pathogenesis of this disease, the development of novel biomarkers of disease progression, and the identification of new potential treatments.
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              Author and article information

              Affiliations
              [1 ]Department of Physiology, Development & Neuroscience, University of Cambridge , Downing Street, Cambridge, CB2 3EG, UK
              Author notes
              [*]

              Present address: Programa de Fisiopatología, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago, Chile.

              Journal
              Journal ID (nlm-ta): Sci Rep
              Journal ID (iso-abbrev): Sci Rep
              Title: Scientific Reports
              Publisher: Nature Publishing Group
              ISSN (Electronic): 2045-2322
              Publication date (Electronic): 16 May 2016
              Publication date Collection 2016
              Volume: 6
              PubMed ID: 27181166
              PMC ID: 4867587
              Publisher Item ID: srep25979
              DOI: 10.1038/srep25979
              Copyright statement: Copyright © 2016, Macmillan Publishers Limited

              License:

              This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/

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