Mechanisms underlying functional deficits and brain pathology in CADASIL/CARASIL

NVC is compromised in both CADASIL and Ang II-induced hypertension models16,21, suggesting possible common mediators (e.g., reactive oxygen species). An elevation of intracellular Ca2+ in the astrocytic processes ("endfeet"), which encase arterioles, triggers vasodilation and, under certain conditions, vasoconstriction10,12. Smooth muscle Notch3ECD is potentially in contact with vascular endothelium and astrocytic endfeet, suggesting the possibility of transcellular communication. Given this architectural relationship, we hypothesize that CADASIL (Notch3) mutations impact NVC through effects on both astrocytes and SMCs. The mechanistic basis for NVC alterations in CADASIL/CARASIL will be examined in brain slices and in vivo by measuring whisker-induced increases in cortical CBF10,12 (Nelson). The relevance of the above findings will be assessed in non-disabled CADASIL patients using functional MRI (fMRI), including arterial spin-labeled (ASL) perfusion MRI and BOLD (blood oxygen level-dependent) MRI, in combination with electroencephalography (EEG) (Chabriat) (collaboration w/Habib Benali, INSERM Paris and Fabrice Wendling, INSERM Rennes, France). These functional deficits may represent early markers of SVD.

Some characteristic histopathological and neurocognitive features of CADASIL may not manifest within the short lifespan of a mouse, even if the molecular mechanisms and their physiological consequences do. This often- encountered limitation of genetic mouse models is commonly circumvented by challenging the system. In this context, we (Ayata) have demonstrated that mutant mouse models of CADASIL, which do not develop spontaneous strokes or white matter degeneration within their normal lifetime, show significantly worse outcomes when challenged by focal cerebral ischemia. We have a number of established experimental mouse models for challenging the cerebral vasculature, including filament or thromboembolic occlusion of the middle cerebral artery, distal occlusion of the middle cerebral artery, acute cerebral microembolism, bilateral common carotid artery stenosis, and stereotactic endothelin microinjection. These models will probe various determinants of acute cerebral ischemic outcome, such as autoregulation, collaterals and neovascularization, parenchymal sensitivity to ischemia, endothelial anti-thrombotic and thrombolytic activity, and blood-brain barrier integrity. The worse outcome and increased susceptibility to CSD in CADASIL may reflect defects in myogenic tone/autoregulation and/or NVC. Importantly, we will test the hypothesis that correcting the defect(s) in autoregulation or NVC (e.g., by blocking upregulated K+ channels) decreases the susceptibility to cardiovascular challenge (Nelson, Ayata).