Angelov et al Elastin Deficiency and SVAS 741 for Eln−/− ELN+/+ mice to better model human elastin haploinsufficiency was suggested by genotype-specific increases in elastic lamina breaks and medial thickening, as well as modestly reduced pressure-normalized ex vivo outer aortic diameters. 23 However, no luminal stenoses were reported in these mice, and SMC proliferation was not investigated. In this issue of ATVB, a report by Jiao et al8 enhances our understanding of the pathogenesis of aortic obstruction associated with elastin deficiency. The authors used a combination of meticulous in vivo, in situ, and ex vivo approaches to investigate the size, structure, and mechanical properties of aortas of (elastin-deficient) Eln−/− ELN+/+ mice (termed human bacterial artificial chromosome [hBAC]-mNull mice by Jiao et al8). Compared with controls, hBAC-mNull aortas had smaller external and internal diameters but were significantly longer and heavier. Postnatal time-course data showed that hBAC-mNull aortas had decreased circumferential growth, but significantly increased axial growth. Compared with aortas of mice with higher levels of elastin, hBAC-mNull aortas also had thicker medias. However, their medial cross-sectional areas were normal, with no increase in number of medial cells per cross section. Reduced circumferential growth of hBAC-mNull aortas (accompanied by secondary medial thickening; Figure [D]) resulted in a large (70%) reduction in ascending aortic lumen area compared with mice with normal or near-normal levels of elastin. This is the most impressive aortic stenosis yet reported in an elastin-haploinsufficient mouse. Although hBAC-mNull aortas were less distensible than control aortas in vivo, this deficit could account for only a small percentage of the observed luminal narrowing. Finally, aortic SMC of hBAC-mNull mice had a higher proliferative rate both in vivo and in culture. Jiao et al8 also examined aortic tissue from a single human WS subject who died suddenly. This aorta had a relatively small external diameter, a thick wall, normal medial area and cell number, loss of elastin, and accumulation of collagen; features that are all shared with the Eln−/− ELN+/+ aortas. The authors concluded that—contrary to widely held models9, 10, 12, 17, 18, 20, 24—increased SMC proliferation is likely not the underlying cause of aortic stenosis and lumen loss associated with elastin haploinsufficiency. Rather, aortic lumen narrowing results from deficient circumferential growth, incidentally accompanied by excess axial growth. Jiao et al’s8 findings are elegant, exciting, and potentially paradigm shifting. Nevertheless, this article raises 2 major—and related—questions, answers to which will determine the longterm impact of this work. The first question is largely clinical: is aortopathy of the Eln−/− ELN+/+ mouse an authentic model of the aortopathy in human SVAS and WS? Jiao et al8 validated their findings in Eln−/− ELN+/+ mice in relation to only 1 human WS specimen. This n= 1 data set precludes confident conclusions,