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Reduced nitric oxide bioavailability mediates cerebroarterial dysfunction independent of cerebral amyloid angiopathy in a mouse model of Alzheimer's disease.
Am J Physiol Heart Circ Physiol. 2017 Feb 01; 312(2):H232-H238.AJ

Abstract

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.

Authors+Show Affiliations

Center for Molecular Cardiology, Schlieren, University of Zurich, and Department of Cardiology, University Heart Center, University Hospital Zurich, Schlieren, Switzerland. Neuroscience Center Zurich, Schlieren, Switzerland.Biomedical Research Center, Zhongshan Hospital, Fudan University, Shanghai, China.Center for Molecular Cardiology, Schlieren, University of Zurich, and Department of Cardiology, University Heart Center, University Hospital Zurich, Schlieren, Switzerland.Department of Medicine, Karolinska University Hospital, Stockholm, Sweden; and.Center for Molecular Cardiology, Schlieren, University of Zurich, and Department of Cardiology, University Heart Center, University Hospital Zurich, Schlieren, Switzerland.Institute for Regenerative Medicine, University of Zurich, Schlieren, Switzerland.Center for Molecular Cardiology, Schlieren, University of Zurich, and Department of Cardiology, University Heart Center, University Hospital Zurich, Schlieren, Switzerland.Neuroscience Center Zurich, Schlieren, Switzerland. Institute for Regenerative Medicine, University of Zurich, Schlieren, Switzerland.Neuroscience Center Zurich, Schlieren, Switzerland. Institute for Regenerative Medicine, University of Zurich, Schlieren, Switzerland.Center for Molecular Cardiology, Schlieren, University of Zurich, and Department of Cardiology, University Heart Center, University Hospital Zurich, Schlieren, Switzerland.Center for Molecular Cardiology, Schlieren, University of Zurich, and Department of Cardiology, University Heart Center, University Hospital Zurich, Schlieren, Switzerland; giovanni.camici@uzh.ch. Neuroscience Center Zurich, Schlieren, Switzerland.

Pub Type(s)

Journal Article
Video-Audio Media

Language

eng

PubMed ID

27836896

Citation

Merlini, Mario, et al. "Reduced Nitric Oxide Bioavailability Mediates Cerebroarterial Dysfunction Independent of Cerebral Amyloid Angiopathy in a Mouse Model of Alzheimer's Disease." American Journal of Physiology. Heart and Circulatory Physiology, vol. 312, no. 2, 2017, pp. H232-H238.
Merlini M, Shi Y, Keller S, et al. Reduced nitric oxide bioavailability mediates cerebroarterial dysfunction independent of cerebral amyloid angiopathy in a mouse model of Alzheimer's disease. Am J Physiol Heart Circ Physiol. 2017;312(2):H232-H238.
Merlini, M., Shi, Y., Keller, S., Savarese, G., Akhmedov, A., Derungs, R., Spescha, R. D., Kulic, L., Nitsch, R. M., Lüscher, T. F., & Camici, G. G. (2017). Reduced nitric oxide bioavailability mediates cerebroarterial dysfunction independent of cerebral amyloid angiopathy in a mouse model of Alzheimer's disease. American Journal of Physiology. Heart and Circulatory Physiology, 312(2), H232-H238. https://doi.org/10.1152/ajpheart.00607.2016
Merlini M, et al. Reduced Nitric Oxide Bioavailability Mediates Cerebroarterial Dysfunction Independent of Cerebral Amyloid Angiopathy in a Mouse Model of Alzheimer's Disease. Am J Physiol Heart Circ Physiol. 2017 Feb 1;312(2):H232-H238. PubMed PMID: 27836896.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Reduced nitric oxide bioavailability mediates cerebroarterial dysfunction independent of cerebral amyloid angiopathy in a mouse model of Alzheimer's disease. AU - Merlini,Mario, AU - Shi,Yi, AU - Keller,Stephan, AU - Savarese,Gianluigi, AU - Akhmedov,Alexander, AU - Derungs,Rebecca, AU - Spescha,Remo D, AU - Kulic,Luka, AU - Nitsch,Roger M, AU - Lüscher,Thomas F, AU - Camici,Giovanni G, Y1 - 2016/11/11/ PY - 2016/09/05/received PY - 2016/11/01/revised PY - 2016/11/10/accepted PY - 2016/11/12/pubmed PY - 2017/6/27/medline PY - 2016/11/13/entrez KW - Alzheimer’s disease KW - cerebral amyloid angiopathy KW - cerebrovascular pathology KW - cyclic GMP KW - endothelial dysfunction KW - nitric oxide SP - H232 EP - H238 JF - American journal of physiology. Heart and circulatory physiology JO - Am. J. Physiol. Heart Circ. Physiol. VL - 312 IS - 2 N2 - : 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. SN - 1522-1539 UR - https://www.unboundmedicine.com/medline/citation/27836896/Reduced_nitric_oxide_bioavailability_mediates_cerebroarterial_dysfunction_independent_of_cerebral_amyloid_angiopathy_in_a_mouse_model_of_Alzheimer's_disease_ L2 - http://www.physiology.org/doi/full/10.1152/ajpheart.00607.2016?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -