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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.
Highlights
Recent evidence shows that the Huntington’s disease (HD) extends beyond the nervous system to other sites, including the cardiovascular system
We investigated in the R6/2 mouse model of HD nitric oxide (NO) dependent and independent endothelial mechanisms
There were no significant differences in the maximal response to sodium nitroprusside (SNP) in any group, suggesting no differences in vascular smooth muscle potential to vasodilate (Fig. 1)
Summary
Recent evidence shows that the Huntington’s disease (HD) extends beyond the nervous system to other sites, including the cardiovascular system. By 16 weeks of adult age, the R6/2 mouse developed overt endothelial dysfunction due to an inability to increase NO dependent vasodilation. In vivo the R6/2 heart is unable to respond positively to β1 adrenergic stimulation[14] Such overt derangements in cardiac function in the R6/2 mouse may be expected to be associated with peripheral vascular dysfunction. Given that HD patients and R6/2 mice display evidence of sympathetic autonomic dominance[8,9,10], we further investigated femoral artery α1-adrenergic constrictor function in addition to NO-dependent and independent dilator function in the R6/2 mouse at 12 and 16 weeks of age, corresponding to early symptomatic and established impaired neurological stages of the disease process, respectively[16]
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