Receptor stoichiometry predicts artery-typical vulnerability to altered Notch signaling during smooth muscle differentiation.
The development and maintenance of arterial smooth muscle cells (SMCs) rely on Jagged1-Notch2/Notch3 signaling. While Notch2 and Notch3 are thought to function redundantly during SMC development, clinical and experimental evidence suggests artery-specific importance for the two receptors. Combining in vitro, in vivo, and in silico models, we report that the canonical Notch signaling during SMC differentiation is largely driven by Notch2. While Notch2 and Notch3 co-regulate a large group of genes in SMCs upon Jagged1 interaction, Notch3 is a less potent inducer of Notch signaling than Notch2 and requires higher doses to potentiate a meaningful transcriptional response due to its weak interaction with RBPJ{kappa}. Consequently, Notch2 depletion abolishes Notch signaling in the SMCs of the large elastic arteries. However, high Jagged1 and Notch3 expression in smaller arteries like those in the brain can compensate for Notch2 loss. This work refines our mechanistic understanding of Notch signaling in the SMCs and offers region-specific insights into the Notch-related arterial diseases.