Dave et al. discovered that JAG1/NOTCH3 signaling in VSMCs was critical for neointimal lesion formation with elastin insufficiency. The mechanism involved changes in DNA methylation, NOTCH3 activation through JAG1, and NOTCH targets including integrin β3 (left). Because cells similar to NOTCH3-expressing SMCs reside in the vascular microenvironment within periaortic fat (16), VSMC-specific loss of JAG1, or global loss of NOTCH3, may affect local adipose-derived paracrine signaling (curved arrows). Recently, Lin et al. depleted elastin in a lineage-specific manner to show that VSMCs derived from the secondary heart field lineage drive neointimal lesion formation (23). VSMCs within pulmonary arteries derive from a separate developmental lineage compared with those within the ascending aorta, and, interestingly, NOTCH3 expression varies, with only a small proportion of pulmonary artery VSMCs having high levels (right). Notably, a critical role was discovered for NOTCH3 in a model of chronic pulmonary inflammation leading to medial thickening, elastin breakdown, and intimal lesion formation (24). After elastin breakdown, founder cells required NOTCH3 to infiltrate and populate the intima, leading to clonal expansion and vascular occlusion (24). It will be of interest to query similar roles for NOTCH3 signaling in other pathologies involving VSMC expansion and intimal lesion formation.