title: Cerebrovascular dysfunction and microcirculation rarefaction precede white matter lesions in a mouse genetic model of cerebral ischemic small vessel disease.
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.
authors.affiliation: INSERM U740, Paris, France. anne.joutel@univparis-diderot.fr
authors.forename: Anne
authors.initials: A
authors.lastname: Joutel
authors.forename: Marie
authors.initials: M
authors.lastname: Monet-Leprêtre
authors.forename: Claudia
authors.initials: C
authors.lastname: Gosele
authors.forename: Céline
authors.initials: C
authors.lastname: Baron-Menguy
authors.forename: Annette
authors.initials: A
authors.lastname: Hammes
authors.forename: Sabine
authors.initials: S
authors.lastname: Schmidt
authors.forename: Barbara
authors.initials: B
authors.lastname: Lemaire-Carrette
authors.forename: Valérie
authors.initials: V
authors.lastname: Domenga
authors.forename: Andreas
authors.initials: A
authors.lastname: Schedl
authors.forename: Pierre
authors.initials: P
authors.lastname: Lacombe
authors.forename: Norbert
authors.initials: N
authors.lastname: Hubner
mesh_terms: D000818:Animals; D001808:Blood Vessels / Q000473:pathology; D001812:Blood-Brain Barrier; D002545:Brain Ischemia / Q000235:genetics* / Q000473:pathology; D046589:CADASIL / Q000235:genetics / Q000473:pathology; D002536:Cerebral Arteries / Q000473:pathology; D002560:Cerebrovascular Circulation / Q000235:genetics*; D022201:Chromosomes, Artificial / Q000235:genetics; D004195:Disease Models, Animal; D018450:Disease Progression; D006706:Homeostasis; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D000071656:Receptor, Notch3; D051880:Receptors, Notch / Q000235:genetics
chemical_list: C499373:Notch3 protein, mouse; D000071656:Receptor, Notch3; D051880:Receptors, Notch