Abstract
Cerebral autosomal dominant arteriopathy, subcortical infarcts, and leukoencephalopathy (CADASIL) is the most common monogenic form of small vessel disease characterized by migraine with aura, leukoaraiosis, strokes, and dementia. CADASIL mutations cause cerebrovascular dysfunction in both animal models and humans. Here, we showed that 2 different human CADASIL mutations (Notch3 R90C or R169C) worsen ischemic stroke outcomes in transgenic mice; this was explained by the higher blood flow threshold to maintain tissue viability compared with that in wild type (WT) mice. Both mutants developed larger infarcts and worse neurological deficits compared with WT mice, regardless of age or sex after filament middle cerebral artery occlusion. However, full-field laser speckle flowmetry during distal middle cerebral artery occlusion showed comparable perfusion deficits in mutants and their respective WT controls. Circle of Willis anatomy and pial collateralization also did not differ among the genotypes. In contrast, mutants had a higher cerebral blood flow threshold, below which infarction ensued, suggesting increased sensitivity of brain tissue to ischemia. Electrophysiological recordings revealed a 1.5- to 2-fold higher frequency of peri-infarct spreading depolarizations in CADASIL mutants. Higher extracellular K+ elevations during spreading depolarizations in the mutants implicated a defect in extracellular K+ clearance. Altogether, these data reveal a mechanism of enhanced vulnerability to ischemic injury linked to abnormal extracellular ion homeostasis and susceptibility to ischemic depolarizations in CADASIL.
Highlights
Cerebral autosomal dominant arteriopathy, subcortical infarcts, and leukoencephalopathy (CADASIL) is the most common monogenic small vessel disease, characterized by frequent migraine attacks with aura, progressive white matter degeneration, and recurrent lacunar infarctions in young to middle-aged adults, culminating in vascular dementia [1]
We first examined the effect of Notch3R90C mutation on the outcome of filament middle cerebral artery occlusion
We have previously shown that CADASIL mutations increase point, indicating that the phenotype was not due to susceptibility to spreading depolarizations (SD), consistent with
Summary
Subcortical infarcts, and leukoencephalopathy (CADASIL) is the most common monogenic small vessel disease, characterized by frequent migraine attacks with aura, progressive white matter degeneration, and recurrent lacunar infarctions in young to middle-aged adults, culminating in vascular dementia [1]. Patients with CADASIL exhibit deficits in functional hyperemia and cerebrovascular reactivity to CO2 that can be present long before evidence of significant disability and cognitive deficits [2, 3]. The disease is caused by highly stereotyped mutations in the NOTCH3 receptor, which is predominantly expressed in pericytes and smooth muscle cells of small vessels [4–6]. A number of genetic mouse models expressing Notch CADASIL mutations have been developed that recapitulate the CADASIL
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