In the current study, we utilize a wide array of elastin deficiency models — knockdown in cultured human vascular cells, genetic and pharmacological inhibition in mouse models, and iPSC-SMCs and aortic samples from nonsyndromic SVAS and/or WBS patients — to demonstrate that the JAG1/NOTCH3/γ-secretase pathway is overactive in SMCs with elastin depletion (Figure 1). Here, ELN is linked to supravalvular aortic stenosis.