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.

Consensus statement for diagnosis of subcortical small vessel disease

“…Notably, analysis of isolated vessels have showed reduced myogenic responses in both pial and parenchymal arteries in mutant mice, a finding that could account for the impaired cerebrovascular reactivity in these mice. 130 Importantly, the data indicate that cerebral arteries are dysfunctional in the absence of overt smooth muscle degeneration and fibrosis, and that cerebrovascular dysfunction is detectable before the appearance of white-matter lesions, suggesting that the former could cause the latter. 130 …”

“…130 Importantly, the data indicate that cerebral arteries are dysfunctional in the absence of overt smooth muscle degeneration and fibrosis, and that cerebrovascular dysfunction is detectable before the appearance of white-matter lesions, suggesting that the former could cause the latter. 130 …”

Hypomorphic Notch 3 alleles link Notch signaling to ischemic cerebral small-vessel disease

“…Both the composition as well as the possible functional consequences of these deposits are unknown (13). Nevertheless, we were encouraged to examine this phenomenon by the reported findings that mice overexpressing Notch 3 receptors carrying different CADASIL mutations develop what are suggested to be deposits analogous to human GOMs in the vasculature (24,29,30).…”

What factors determine phenotype of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL)? Considerations in the context of a novel pathogenic R110C mutation in the NOTCH3 gene

“…Although qualitative or semi-quantitative changes in GOM do not correlate directly with patients' age [10], there are some data indicating a possible relationship of the deposits with progression of histopathological changes in CADASIL. GOM deposits are very early alterations whose development precedes detectable morphological changes in cerebral vessels [4] but not their dysfunction [14]. In a human fetus with a mutated NOTCH3 gene, GOM deposits were not found [5], but they started to be observed in patients at the age of 20 years [6], and then, after a period in which the number GOM deposits was relatively constant, their number gradually decreased with duration of the disease.…”