Selective vulnerability of cerebral vasculature to NOTCH3 variants in small vessel disease and rescue by phosphodiesterase-5 inhibitor - PubMed
4 hours ago
- #NOTCH3
- #small vessel disease
- #CADASIL
- NOTCH3 variants cause CADASIL, a common monogenic form of small vessel disease and vascular dementia, with unclear molecular mechanisms and no current treatments.
- Human iPSC models revealed that cerebral vascular smooth muscle cells (VSMCs) are selectively vulnerable to NOTCH3 variants, unlike peripheral VSMCs, due to differences in embryonic origins.
- CADASIL iPSC-derived brain VSMCs adopt a synthetic phenotype, leading to extracellular matrix accumulation, impaired cell adhesion, and anoikis.
- Endothelial-independent nitric oxide signaling is significantly impaired in these mutant VSMCs.
- Phosphodiesterase-5 inhibition reversed functional abnormalities and improved survival of the mutant VSMCs, suggesting a potential therapeutic strategy for NOTCH3-associated small vessel disease and vascular dementia.