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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., Introduction Ischemic cerebral small vessel disease (SVD) is the leading cause of vascular dementia and a major contributor to stroke in humans. Most ischemic cerebral SVDs involve a diffuse arteriopathy [...]

Notch3 is required to generate functional arteries in mice by regulating arterial differentiation and maturation of vascular smooth muscle cells (vSMC) and that Notch3 is required for arterial specification of vSMC but not of endothelial cells. The data from observation on Notch3 mice reveal Notch3 to be first cell-autonomous regulator of arterial differentiation and maturation of vSMC.

Notch3 receptor (Notch3R) highly implicated in the mechanisms of vascular differentiation plays a key role in the control of arterial integrity. Notch3R KO vascular smooth muscle cells exhibited marked alterations in shape and size. The goal of this study was to analyse the physiological consequences of these morphological alterations. Mesenteric and tail caudal arteries were isolated from 5 KO and 6 WT mice, 12 weeks old, to be analysed on pressure and wire myographs. Passive diameter (PD) from tail artery was similar in both strains (WT: 243 ± 12 vs KO: 217 ± 12 µm). Nevertheless myogenic tone was significantly reduced (77 %) in KO (WT: 32.2 ± 3.7 vs. KO: 10.7 ± 2.1 % of PD 75 mmHg. P<0.05). This was associated to a significant improvement of the flow-mediated dilation. (86 % for a 50 µL/min flow, WT 44.6 ± 5.0 vs. 86.7 ± 5.2 % dilation, P<0.001). Tail artery from KO mice exhibited also an increased phenylephrine-induced constriction but no change in ACh-induced dilation. In mesenteric artery, vascular mechano-transduction was not affected by the depletion in Notch3R. However in this latter artery ACh-induced dilation was reduced. This study clearly showed the predominant role played by Notch3R in the control of vascular mechano-transduction with opposite effects on myogenic tone and flow mediated dilation. Notch3R might thus have a key role in the control of vascular mechano-transduction of muscular arteries. The pathophysiologic consequences of this observation have to be determined. [ABSTRACT FROM AUTHOR]