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Reduced nitric oxid...
Reduced nitric oxide bioavailability mediates cerebroarterial dysfunction independent of cerebral amyloid angiopathy in a mouse model of Alzheimer's disease
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Merlini, M (author)
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Shi, Y (author)
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Keller, S (author)
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- Savarese, G (author)
- Karolinska Institutet
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Akhmedov, A (author)
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Derungs, R (author)
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Spescha, RD (author)
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Kulic, L (author)
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Nitsch, RM (author)
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Luscher, TF (author)
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Camici, GG (author)
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(creator_code:org_t)
- American Physiological Society, 2017
- 2017
- English.
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In: American journal of physiology. Heart and circulatory physiology. - : American Physiological Society. - 1522-1539 .- 0363-6135. ; 312:2, s. H232-H238
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https://doi.org/10.1...
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Abstract
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- In Alzheimer’s disease (AD), cerebral arteries, in contrast to cerebral microvessels, show both cerebral amyloid angiopathy (CAA) -dependent and -independent vessel wall pathology. However, it remains unclear whether CAA-independent vessel wall pathology affects arterial function, thereby chronically reducing cerebral perfusion, and, if so, which mechanisms mediate this effect. To this end, we assessed the ex vivo vascular function of the basilar artery and a similar-sized peripheral artery (femoral artery) in the Swedish-Arctic (SweArc) transgenic AD mouse model at different disease stages. Furthermore, we used quantitative immunohistochemistry to analyze CAA, endothelial morphology, and molecular pathways pertinent to vascular relaxation. We found that endothelium-dependent, but not smooth muscle-dependent, vasorelaxation was significantly impaired in basilar and femoral arteries of 15-mo-old SweArc mice compared with that of age-matched wild-type and 6-mo-old SweArc mice. This impairment was accompanied by significantly reduced levels of cyclic GMP, indicating a reduced nitric oxide (NO) bioavailability. However, no age- and genotype-related differences in oxidative stress as measured by lipid peroxidation were observed. Although parenchymal capillaries, arterioles, and arteries showed abundant CAA in the 15-mo-old SweArc mice, no CAA or changes in endothelial morphology were detected histologically in the basilar and femoral artery. Thus our results suggest that, in this AD mouse model, dysfunction of large intracranial, extracerebral arteries important for brain perfusion is mediated by reduced NO bioavailability rather than by CAA. This finding supports the growing body of evidence highlighting the therapeutic importance of targeting the cerebrovasculature in AD. NEW & NOTEWORTHY We show that vasorelaxation of the basilar artery, a large intracranial, extracerebral artery important for cerebral perfusion, is impaired independent of cerebral amyloid angiopathy in a transgenic mouse model of Alzheimer’s disease. Interestingly, this dysfunction is specifically endothelium related and is mediated by impaired nitric oxide–cyclic GMP bioavailability. Listen to this article’s corresponding podcast at http://ajpheart.podbean.com/e/cerebroarterial-dysfunction-in-swedish-arctic-ad-mice/ .
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- By the author/editor
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Merlini, M
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Shi, Y
-
Keller, S
-
Savarese, G
-
Akhmedov, A
-
Derungs, R
-
show more...
-
Spescha, RD
-
Kulic, L
-
Nitsch, RM
-
Luscher, TF
-
Camici, GG
-
show less...
- Articles in the publication
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American journal ...
- By the university
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Karolinska Institutet