Proteins of the Notch family are cell surface receptors that transduce signals 
between neighbouring cells. The Notch signalling pathway is highly 
evolutionarily conserved and critical for cell fate determination during 
embryonic development, including many aspects of vascular development. The 
interaction of Notch receptors with ligands leads to cleavage of the Notch 
intracellular domain (NICD) which then translocates to the nucleus and activates 
the transcription factor CBF1/JBP-Jkappa, regulating downstream gene expression. 
To date four Notch receptors have been found in mammals. Of these, Notch3 is 
predominantly expressed in adult arterial smooth muscle cells in human. NOTCH3 
gene mutations cause the autosomal dominant condition, cerebral autosomal 
dominant arteriopathy with subcortical infarcts and leukoecephelopathy 
(CADASIL), an inherited early stroke syndrome leading to dementia due to 
systemic vascular degeneration. This suggests that Notch3 plays a critical role 
in maintaining the phenotypic stability of vascular smooth muscle cells (VSMCs). 
Recent publications indicate that Notch3 is involved in vascular injury and is a 
determinant of VSMC survival, but its exact function is unknown. The molecular 
mechanisms underlying CADASIL pathology are therefore intriguing. Investigation 
of CADASIL mutant Notch3 shows that the majority of mutations do not change 
CBF1/JBP-Jkappa mediated classic Notch activation, so the pathological 
consequences of NOTCH3 mutations in CADASIL patients can not be simply explained 
by loss- or gain-of-function in the classic Notch signalling pathway. This 
suggests that a novel Notch3-mediated signalling pathway may be present in 
VSMCs, or cross-regulation of Notch3 to other signalling pathway(s) may play a 
critical role on VSMCs survival. Alternatively, the mutant Notch3 may gain a 
novel or toxic function in VSMCs. This review will focus on recent findings of 
Notch3 in vascular development and in regulating the VSMC behaviour and 
phenotype, and will use findings on investigating the molecular pathology of the 
single gene disorder CADASIL to understand the function of Notch3 in VSMCs.