NDLI: Cerebrovascular dysfunction and microcirculation rarefaction precede white matter lesions in a mouse genetic model of cerebral ischemic small vessel disease.

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Cerebrovascular dysfunction and microcirculation rarefaction precede white matter lesions in a mouse genetic model of cerebral ischemic small vessel disease.

Content Provider	Semantic Scholar
Author	Joutel, Anne Monet-Leprêtre, Marie Gosele, Claudia Baron-Menguy, Céline Hammes, Annette Schmidt, Sabine Lemaire-Carrette, Barbara Domenga, Valérie Schedl, Andreas Lacombe, Pierre Hubner, Norbert
Copyright Year	2010
Abstract	Cerebral ischemic small vessel disease (SVD) is the leading cause of vascular dementia and a major contributor to stroke in humans. Dominant mutations in NOTCH3 cause cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), a genetic archetype of cerebral ischemic SVD. Progress toward understanding the pathogenesis of this disease and developing effective therapies has been hampered by the lack of a good animal model. Here, we report the development of a mouse model for CADASIL via the introduction of a CADASIL-causing Notch3 point mutation into a large P1-derived artificial chromosome (PAC). In vivo expression of the mutated PAC transgene in the mouse reproduced the endogenous Notch3 expression pattern and main pathological features of CADASIL, including Notch3 extracellular domain aggregates and granular osmiophilic material (GOM) deposits in brain vessels, progressive white matter damage, and reduced cerebral blood flow. Mutant mice displayed attenuated myogenic responses and reduced caliber of brain arteries as well as impaired cerebrovascular autoregulation and functional hyperemia. Further, we identified a substantial reduction of white matter capillary density. These neuropathological changes occurred in the absence of either histologically detectable alterations in cerebral artery structure or blood-brain barrier breakdown. These studies provide in vivo evidence for cerebrovascular dysfunction and microcirculatory failure as key contributors to hypoperfusion and white matter damage in this genetic model of ischemic SVD.
Starting Page	1837
Ending Page	1848
Page Count	12
File Format	PDF HTM / HTML
Alternate Webpage(s)	https://www.jci.org/articles/view/39733/version/2/pdf/render
Alternate Webpage(s)	http://edoc.mdc-berlin.de/10673/1/10673oa.pdf
PubMed reference number	20071773v1
Alternate Webpage(s)	https://doi.org/10.1172/JCI39733
DOI	10.1172/jci39733
Journal	The Journal of clinical investigation
Volume Number	120
Issue Number	2
Language	English
Access Restriction	Open
Subject Keyword	Arteries Arteriopathic disease Autosomal dominant inheritance Binswanger Disease Blood - brain barrier anatomy Blood Vessel Blood capillaries CADASIL Syndrome Catabolism Cerebrovascular Circulation Cerebrovascular Disorders Cerebrovascular system Chromosomes, Artificial Dementia Dementia, Vascular Diameter (qualifier value) Homeostasis Hyperemia Infarction Leukocytes Leukoencephalopathies Liver Failure, Acute Microcirculation NOTCH3 gene P1 Bacteriophage Artificial Chromosomes Parkinson Disease Point Mutation Snowflake vitreoretinal degeneration Structure of cerebral artery T-Cell Large Granular Lymphocyte Leukemia White matter Wolff-Parkinson-White Syndrome hypoperfusion
Content Type	Text
Resource Type	Article

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Cerebral hemodynamics and white matter hyperintensities in CADASIL.

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Cerebrovascular dysfunction and microcirculation rarefaction precede white matter lesions in a mouse genetic model of cerebral ischemic small vessel disease.

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Cerebrovascular dysfunction and microcirculation rarefaction precede white matter lesions in a mouse genetic model of cerebral ischemic small vessel disease

Cerebrovascular dysfunction and microcirculation rarefaction precede white matter lesions in a mouse genetic model of cerebral ischemic small vessel disease.

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