Data from: Selective vulnerability of cerebral vasculature to NOTCH3 variants in small vessel disease and rescue by phosphodiesterase-5 inhibitor

NOTCH3 variants cause CADASIL, the most common genetic form of small
vessel disease (SVD) and vascular dementia (VaD), and increase the stroke
and SVD/VaD risk. CADASIL is a systemic vasculopathy but predominantly
manifests in the brain. The molecular mechanisms of CADASIL remain largely
unclear with no specific available treatments. NOTCH3 is primarily
expressed in vascular smooth muscle cells (VSMCs). Using human induced
pluripotent stem cell (iPSC) models and developmental lineage-specific
VSMC differentiation, we revealed a selective vulnerability of cerebral
but not peripheral VSMC mimics to NOTCH3 variants. Transcriptomic, protein
and functional analyses demonstrated a switching of CADASIL iPSC-VSMCs
from a contractile to a synthetic phenotype, accompanied with extensive
extracellular matrix accumulation and impairment of cell adhesion leading
to anoikis. Importantly, we describe an endothelial independent nitric
oxide signalling in VSMCs which was dysregulated in the CADASIL
iPSC-VSMCs, and posphodiesterase-5 (PDE5) inhibition successfully rescued
the abnormal VSMC function, suggesting a novel therapeutic strategy. Our
findings offer new mechanistic insights into brain specific phenotype in
NOTCH3-associated SVD/VaD and support patient-specific iPSCs to be a
valuable model for identifying targeted treatment for NOTCH3-associated
SVD/VaD.