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

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Authors
Kane, Andrew D 
Niu, Youguo 
Herrera, Emilio A 
Morton, A Jennifer 
Giussani, Dino A 
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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Keywords
Animals, Disease Models, Animal, Femur, Humans, Huntington Disease, Male, Mice, Mice, Transgenic, Myography, Nitric Oxide, Vasodilation
Journal Title
Sci Rep
Conference Name
Journal ISSN
2045-2322
2045-2322
Volume Title
6
Publisher
Springer Science and Business Media LLC
Sponsorship
Biotechnology and Biological Sciences Research Council (BB/E002668/1)
British Heart Foundation (None)
British Heart Foundation (None)
British Heart Foundation (None)
British Heart Foundation (None)
British Heart Foundation (None)
Dino Giussani is the Professor of Cardiovascular Developmental Physiology & Medicine at the Department of Physiology Development & Neuroscience at the University of Cambridge, Professorial Fellow and Director of Studies in Medicine at Gonville & Caius College, a Lister Institute Fellow and a Royal Society Wolfson Research Merit Award Holder. He is supported by the British Heart Foundation. Jenny Morton is Professor of Neurobiology at the Department of Physiology Development & Neuroscience at the University of Cambridge, Professorial Fellow and Director of Studies in Medicine at Newnham College. Her work is funded by CHDI Inc. (USA).