Cerebral autosomal dominant arteriopathy with subcortical infarcts and 
leukoencephalopathy (CADASIL) is a vascular dementing disease caused by 
mutations in the NOTCH3 gene, most which are missense mutations leading to an 
uneven number of cysteine residues in epidermal growth factor-like repeats in 
the extracellular domain of Notch3 receptor (N3ECD). CADASIL is characterized by 
degeneration of vascular smooth muscle cells (VSMC) and accumulation of N3ECD on 
the VSMCs of small and middle-sized arteries. Recent studies have demonstrated 
that impairment of Notch3 signaling is not the primary cause of the disease. In 
the present study we used proteomic analysis to characterize the protein 
expression pattern of a unique material of genetically genuine cultured human 
CADASIL VSMCs. We identified 11 differentially expressed proteins, which are 
involved in protein degradation and folding, contraction of VSMCs, and cellular 
stress. Our findings indicate that misfolding of Notch3 may cause endoplasmic 
reticulum stress and activation of unfolded protein response, leading to 
increased reactive oxygen species and inhibition of cell proliferation. In 
addition, upregulation of contractile proteins suggests an alteration in the 
signaling system of VSMC contraction. The accumulation of N3ECD on the cell 
surface possibly upregulates the angiotensin II regulatory feedback loop and 
thereby enhances the readiness of the cells to respond to angiotensin II 
stimulation.